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Stem cells grown in labs for experimental therapies pose a cancer risk

Around one-fifth of the stem cells grown in laboratories for as-yet-unapproved medical treatments have cancer-causing mutations

By Clare Wilson

19 February 2024

stem cell therapy research articles

Stem cells can be obtained from unneeded embryos made during in vitro fertilisation

nobeastsofierce Science / Alamy

A kind of stem cell transplant that has long been seen as one of the most promising new kinds of medical treatments could bring a greater risk of cancer than we previously thought. A study has found that more than a fifth of stem cells being grown in laboratories for regenerative medicine research harbour cancer-causing mutations.

The cells tested haven’t been put into people, but were being used in research to explore their medical use. The findings show…

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Stem cells ‘migrate’ to repair damaged lung cells, study shows.

A new Yale-led study has found that stem cells migrate to help repair damaged lung cells caused by injuries such as viral or bacterial infections.

The findings were published Feb. 19 in the journal Developmental Cell .

“ This is an exciting new insight into stem cell biology,” said Maurizio Chioccioli , assistant professor of genetics and comparative medicine at Yale School of Medicine and corresponding author of the paper.

For the study, the researchers looked at the two main cell types that make up the alveolar epithelium in living mice. Alveolar epithelial type 1 cells, which line lung tissues, are crucial to the exchange of oxygen and carbon dioxide gases. And alveolar type 2 cells or (AT2s) are known to act as stem cells to replenish those injured or dead epithelial cells in the alveoli, or air sacs, in the lung. It was unknown exactly how the AT2s accomplished this feat.

Using advanced timelapse imaging techniques and genetic mouse models, the research team was able to track the fate of individual AT2s in the live breathing intact lung in response to injury. They were able to show for the first time that a large fraction of alveolar stem cells (AT2s) migrate to the site of the injury.

This behavior is important in the regeneration of alveoli, the air sacks that function as the site of gas exchange in the lung, the researchers say.

“ The results demonstrate that stem cell migration between individual functional units is an important driver of tissue regeneration in the mammalian lung,” Chioccioli said.

Other Yale authors of the study include Caroline Hendry , Maor Sauler , Naftali Kaminski , and  Smita Krishnaswamy .

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Stem cells: what they are and what they do.

Stem cells offer great promise for new medical treatments. Learn about stem cell types, current and possible uses, and the state of research and practice.

You've heard about stem cells in the news, and perhaps you've wondered if they might help you or a loved one with a serious disease. You may wonder what stem cells are, how they're being used to treat disease and injury, and why they're the subject of such vigorous debate.

Here are some answers to frequently asked questions about stem cells.

What are stem cells?

Stem cells as the body's master cells

Stem cells: The body's master cells

Stem cells are the body's master cells. All other cells arise from stem cells, including blood cells, nerve cells and others.

Stem cells are the body's raw materials — cells from which all other cells with specialized functions are generated. Under the right conditions in the body or a laboratory, stem cells divide to form more cells called daughter cells.

These daughter cells become either new stem cells or specialized cells (differentiation) with a more specific function, such as blood cells, brain cells, heart muscle cells or bone cells. No other cell in the body has the natural ability to generate new cell types.

Why is there such an interest in stem cells?

Researchers hope stem cell studies can help to:

  • Increase understanding of how diseases occur. By watching stem cells mature into cells in bones, heart muscle, nerves, and other organs and tissue, researchers may better understand how diseases and conditions develop.

Generate healthy cells to replace cells affected by disease (regenerative medicine). Stem cells can be guided into becoming specific cells that can be used in people to regenerate and repair tissues that have been damaged or affected by disease.

People who might benefit from stem cell therapies include those with spinal cord injuries, type 1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, heart disease, stroke, burns, cancer and osteoarthritis.

Stem cells may have the potential to be grown to become new tissue for use in transplant and regenerative medicine. Researchers continue to advance the knowledge on stem cells and their applications in transplant and regenerative medicine.

Test new drugs for safety and effectiveness. Before using investigational drugs in people, researchers can use some types of stem cells to test the drugs for safety and quality. This type of testing will most likely first have a direct impact on drug development for cardiac toxicity testing.

New areas of study include the effectiveness of using human stem cells that have been programmed into tissue-specific cells to test new drugs. For the testing of new drugs to be accurate, the cells must be programmed to acquire properties of the type of cells targeted by the drug. Techniques to program cells into specific cells are under study.

For instance, nerve cells could be generated to test a new drug for a nerve disease. Tests could show whether the new drug had any effect on the cells and whether the cells were harmed.

Where do stem cells come from?

There are several sources of stem cells:

Embryonic stem cells. These stem cells come from embryos that are 3 to 5 days old. At this stage, an embryo is called a blastocyst and has about 150 cells.

These are pluripotent (ploo-RIP-uh-tunt) stem cells, meaning they can divide into more stem cells or can become any type of cell in the body. This versatility allows embryonic stem cells to be used to regenerate or repair diseased tissue and organs.

Adult stem cells. These stem cells are found in small numbers in most adult tissues, such as bone marrow or fat. Compared with embryonic stem cells, adult stem cells have a more limited ability to give rise to various cells of the body.

Until recently, researchers thought adult stem cells could create only similar types of cells. For instance, researchers thought that stem cells residing in the bone marrow could give rise only to blood cells.

However, emerging evidence suggests that adult stem cells may be able to create various types of cells. For instance, bone marrow stem cells may be able to create bone or heart muscle cells.

This research has led to early-stage clinical trials to test usefulness and safety in people. For example, adult stem cells are currently being tested in people with neurological or heart disease.

Adult cells altered to have properties of embryonic stem cells. Scientists have successfully transformed regular adult cells into stem cells using genetic reprogramming. By altering the genes in the adult cells, researchers can reprogram the cells to act similarly to embryonic stem cells.

This new technique may allow use of reprogrammed cells instead of embryonic stem cells and prevent immune system rejection of the new stem cells. However, scientists don't yet know whether using altered adult cells will cause adverse effects in humans.

Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells experienced improved heart function and survival time.

Perinatal stem cells. Researchers have discovered stem cells in amniotic fluid as well as umbilical cord blood. These stem cells have the ability to change into specialized cells.

Amniotic fluid fills the sac that surrounds and protects a developing fetus in the uterus. Researchers have identified stem cells in samples of amniotic fluid drawn from pregnant women for testing or treatment — a procedure called amniocentesis.

Why is there a controversy about using embryonic stem cells?

Embryonic stem cells are obtained from early-stage embryos — a group of cells that forms when eggs are fertilized with sperm at an in vitro fertilization clinic. Because human embryonic stem cells are extracted from human embryos, several questions and issues have been raised about the ethics of embryonic stem cell research.

The National Institutes of Health created guidelines for human stem cell research in 2009. The guidelines define embryonic stem cells and how they may be used in research, and include recommendations for the donation of embryonic stem cells. Also, the guidelines state that embryonic stem cells from embryos created by in vitro fertilization can be used only when the embryo is no longer needed.

Where do these embryos come from?

The embryos being used in embryonic stem cell research come from eggs that were fertilized at in vitro fertilization clinics but never implanted in women's uteruses. The stem cells are donated with informed consent from donors. The stem cells can live and grow in special solutions in test tubes or petri dishes in laboratories.

Why can't researchers use adult stem cells instead?

Although research into adult stem cells is promising, adult stem cells may not be as versatile and durable as are embryonic stem cells. Adult stem cells may not be able to be manipulated to produce all cell types, which limits how adult stem cells can be used to treat diseases.

Adult stem cells are also more likely to contain abnormalities due to environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, researchers have found that adult stem cells are more adaptable than was first thought.

What are stem cell lines and why do researchers want to use them?

A stem cell line is a group of cells that all descend from a single original stem cell and are grown in a lab. Cells in a stem cell line keep growing but don't differentiate into specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or shared with other researchers.

What is stem cell therapy (regenerative medicine) and how does it work?

Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. It is the next chapter in organ transplantation and uses cells instead of donor organs, which are limited in supply.

Researchers grow stem cells in a lab. These stem cells are manipulated to specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells.

The specialized cells can then be implanted into a person. For example, if the person has heart disease, the cells could be injected into the heart muscle. The healthy transplanted heart muscle cells could then contribute to repairing the injured heart muscle.

Researchers have already shown that adult bone marrow cells guided to become heart-like cells can repair heart tissue in people, and more research is ongoing.

Have stem cells already been used to treat diseases?

Yes. Doctors have performed stem cell transplants, also known as bone marrow transplants. In stem cell transplants, stem cells replace cells damaged by chemotherapy or disease or serve as a way for the donor's immune system to fight some types of cancer and blood-related diseases, such as leukemia, lymphoma, neuroblastoma and multiple myeloma. These transplants use adult stem cells or umbilical cord blood.

Researchers are testing adult stem cells to treat other conditions, including a number of degenerative diseases such as heart failure.

What are the potential problems with using embryonic stem cells in humans?

For embryonic stem cells to be useful, researchers must be certain that the stem cells will differentiate into the specific cell types desired.

Researchers have discovered ways to direct stem cells to become specific types of cells, such as directing embryonic stem cells to become heart cells. Research is ongoing in this area.

Embryonic stem cells can also grow irregularly or specialize in different cell types spontaneously. Researchers are studying how to control the growth and differentiation of embryonic stem cells.

Embryonic stem cells might also trigger an immune response in which the recipient's body attacks the stem cells as foreign invaders, or the stem cells might simply fail to function as expected, with unknown consequences. Researchers continue to study how to avoid these possible complications.

What is therapeutic cloning, and what benefits might it offer?

Therapeutic cloning, also called somatic cell nuclear transfer, is a technique to create versatile stem cells independent of fertilized eggs. In this technique, the nucleus is removed from an unfertilized egg. This nucleus contains the genetic material. The nucleus is also removed from the cell of a donor.

This donor nucleus is then injected into the egg, replacing the nucleus that was removed, in a process called nuclear transfer. The egg is allowed to divide and soon forms a blastocyst. This process creates a line of stem cells that is genetically identical to the donor's cells — in essence, a clone.

Some researchers believe that stem cells derived from therapeutic cloning may offer benefits over those from fertilized eggs because cloned cells are less likely to be rejected once transplanted back into the donor and may allow researchers to see exactly how a disease develops.

Has therapeutic cloning in people been successful?

No. Researchers haven't been able to successfully perform therapeutic cloning with humans despite success in a number of other species.

However, in recent studies, researchers have created human pluripotent stem cells by modifying the therapeutic cloning process. Researchers continue to study the potential of therapeutic cloning in people.

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  • Stem cell basics. National Institutes of Health. https://stemcells.nih.gov/info/basics/stc-basics/#stc-I. Accessed Jan. 21, 2022.
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Evaluation of the Efficacy of Stem Cells Therapy in the Periodontal Regeneration: A Meta-Analysis and Mendelian Randomization Study

  • Published: 22 February 2024

Cite this article

  • Jing Hu 1 ,
  • Ze-Yue Ou-Yang 1 ,
  • Ya-Qiong Zhao 1 ,
  • Jie Zhao 1 ,
  • Qiong Liu 1 ,
  • Min-yuan Wang 1 ,
  • Yao Feng 1 ,
  • Meng-Mei Zhong 1 ,
  • Ning-Xin Chen 1 ,
  • Xiao-Lin Su 1 ,
  • Qian Zhang 1 ,
  • Yun-Zhi Feng 1 &
  • Yue Guo   ORCID: orcid.org/0000-0003-2403-2034 1  

16 Accesses

Explore all metrics

Stem cell therapy for periodontal defects has shown good promise in preclinical studies. The purpose of this study was to evaluate the impact of stem cell support on the regeneration of both soft and hard tissues in periodontal treatment. PubMed, Cochrane Library, Embase, and Web of Science were searched and patients with periodontal defects who received stem cell therapy were included in this study. The quality of the included articles was assessed using Cochrane’s tool for evaluating bias, and heterogeneity was analyzed using the I 2 method. An Mendelian randomization investigation was conducted using abstract data from the IEU public databases obtained through GWAS. Nine articles were included for the meta-analysis. Stem cell therapy effectively rebuilds periodontal tissues in patients with periodontal defects, as evidenced by a reduction in probing depth, clinical attachment level  and bone defect depth . And delta-like homolog 1 is a protective factor against periodontal defects alternative indicator of tooth loosening. The findings of this research endorse the utilization of stem cell treatment for repairing periodontal defects in individuals suffering from periodontitis. It is recommended that additional extensive clinical investigations be carried out to validate the efficacy of stem cell therapy and encourage its widespread adoption.

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Data Availability

The datasets generated and/or analyzed during the current study are available in the IEU Open GWAS Project, [ http://gwas.mrcieu.ac.uk ].

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Acknowledgements

This work was supported by the National Natural Science Foundation of China [81800788 and 81773339], Science and Technology Department of Hunan Province, China [2017WK2041 and 2018SK52511], Scientific Research Project of Hunan Provincial Health Commission [202208043514], Natural Science Foundation of Hunan Province [2022JJ30062], Natural Science Foundation of Changsha City [kq2202403 and kq2202412], Education and Teaching Reform Research Project of Central South University [2020jy165-3].

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Jing Hu, Ze-Yue Ou-Yang, Ya-Qiong Zhao, Jie Zhao, Li Tan, Qiong Liu, Min-yuan Wang, Qin Ye, Yao Feng, Meng-Mei Zhong, Ning-Xin Chen, Xiao-Lin Su, Qian Zhang, Yun-Zhi Feng & Yue Guo

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Jing Hu: contributed to the conceptualization, formal analysis, data curation, writing-original draft preparation. Ze-Yue Ou-Yang was a major contributor in methodology, software, writing- reviewing and editing. Ya-Qiong Zhao, Jie Zhao performed the visualization. Li Tan, Qiong Liu, Min-yuan Wang, Qin Ye, Yao Feng, Meng-Mei Zhong, Ning-Xin Chen, Xiao-Lin Su, Qian Zhang, Yun-Zhi Feng and Yue Guo read and approved the final manuscript.

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Supplementary Information

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12015_2024_10690_MOESM1_ESM.png

Supplementary file1 (PNG 370 KB) (A, C, E, G) Funnel plot of meta-analyses of PD, CAL, BDD, GR, (B, D, F, H) and sensitivity analysis of the effects of meta-analyses of PD, CAL, BDD, GR.

12015_2024_10690_MOESM2_ESM.png

Supplementary file2 (PNG 338 KB) (A) Comparison between autologous stem cell therapy versus therapy without autologous stem cell in terms of PD; (B) Subgroup analysis according to 3-, 6- and 12-month follow-up results of PD. "a", "b" and "d" subscript letters next to the year of study denotes different follow-up time groups within the same study. "1" and "2" subscript number next to the year of study: denotes different treatment groups within the same study.

12015_2024_10690_MOESM3_ESM.png

Supplementary file3 (PNG 311 KB) (A) Comparison between autologous stem cell therapy versus therapy without autologous stem cell in terms of CAL; (B) Subgroup analysis according to 3-, 6- and 12-month follow-up results of CAL. "a", "b" and "d" subscript letters next to the year of study denotes different follow-up time groups within the same study.

12015_2024_10690_MOESM4_ESM.png

Supplementary file4 (PNG 265 KB) Comparison between autologous stem cell therapy versus therapy without autologous stem cell in terms of BDD; (B) Subgroup analysis according to 3-, 6- and 12-month follow-up results of BDD. "a", "b" and "d" subscript letters next to the year of study denotes different follow-up time groups within the same study.

12015_2024_10690_MOESM5_ESM.png

Supplementary file5 (PNG 308 KB) Comparison between autologous stem cell therapy versus therapy without autologous stem cell in terms of GR; (B) Subgroup analysis according to 3-, 6- and 12-month follow-up results of GR. "a", "b" and "d" subscript letters next to the year of study denotes different follow-up time groups within the same study. "1" and "2" subscript number next to the year of study: denotes different treatment groups within the same study.

Supplementary file6 (PNG 216 KB) Leave-one-out plot.

Supplementary file7 (png 158 kb) funnel plot of snps associated with dlk1 and their risk of loose teeth., supplementary file8 (docx 19 kb) table s1: literature search format., 12015_2024_10690_moesm9_esm.docx.

Supplementary file9 (DOCX 39 KB) Table S2 STROBE-MR checklist of recommended items to address in reports of Mendelian randomization studies

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Hu, J., Ou-Yang, ZY., Zhao, YQ. et al. Evaluation of the Efficacy of Stem Cells Therapy in the Periodontal Regeneration: A Meta-Analysis and Mendelian Randomization Study. Stem Cell Rev and Rep (2024). https://doi.org/10.1007/s12015-024-10690-x

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Stem cell-based therapies for ischemic stroke: a systematic review and meta-analysis of clinical trials

  • Zhonghao Li 1 ,
  • Xiaoke Dong 1 ,
  • Min Tian 2 ,
  • Chongchong Liu 1 ,
  • Kaiyue Wang 1 ,
  • Lili Li 1 ,
  • Zunjing Liu   ORCID: orcid.org/0000-0002-7962-8217 2 &
  • Jinmin Liu 1  

Stem Cell Research & Therapy volume  11 , Article number:  252 ( 2020 ) Cite this article

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Recently, extensive researches about stem cell-based therapies for ischemic stroke have been published; our review evaluated the efficacy and safety of stem cell-based therapies for ischemic stroke. Our review was registered on PROSPERO ( http://www.crd.york.ac.uk/PROSPERO ), registration number CRD42019135805. Two independent observers searched PubMed, EMBASE, Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials), and Web of Science (Science Citation Index Expanded) for relevant studies up to 31 May 2019. We included clinical trials which compared efficacy outcomes (measured by National Institutes of Health Stroke Scale (NIHSS), modified Rankin scale (mRS), or Barthel index (BI)) and safety outcomes (such as death and adverse effects) between the stem cell-based therapies and control in ischemic stroke. We performed random effect meta-analysis using Review Manager 5.3. Our review included nine randomized controlled trials (RCTs) and seven non-randomized studies (NRSs), involving 740 participants. Stem cell-based therapies were associated with better outcomes measured by NIHSS (mean difference (MD) − 1.63, 95% confidence intervals (CI) − 2.73 to − 0.53, I 2  =60%) and BI (MD 14.68, 95% CI 1.12 to 28.24, I 2  = 68%) in RCTs, and by BI (MD 6.40, 95% CI 3.14 to 9.65, I 2  = 0%) in NRSs. However, the risk of bias was high and the efficacy outcomes of RCTs were high heterogeneity. There was no significant difference in mortality between the stem cell group and the control group. Fever, headache, and recurrent stroke were the most frequently reported adverse effects. Our review shows that stem cell-based therapies can improve the neurological deficits and activities of daily living in patients with ischemic stroke.

Introduction

Stroke is the second most common cause of death and disability in the world, leading to a heavy burden on patients, family, and society [ 1 ]. As a predominant stroke subtype, ischemic stroke constituted 69.6% among all subtypes of incident stroke according to the national epidemiological survey of stroke in China [ 2 ]. At present, intravenous recombinant tissue plasminogen activator and endovascular mechanical thrombectomy are effective at the hyperacute phase, but they are hampered by the narrow time window and strict indications [ 3 , 4 ]. Patients who fail to receive these managements may be left with a residual deficit. Although rehabilitation can aid functional recovery and brain reorganization, the effects are still limited [ 5 ]. Pharmacological attempts to stimulate repair and neuroprotection have been widely investigated in experimental studies but few have been effective in clinical use [ 6 ]. More therapeutic approaches are needed.

Infarction causes an acute loss of different cells such as neurons and glial cells in the brain. The initial stem cell-based therapies were aimed toward a cell replacement strategy and have been demonstrated in laboratory [ 7 ]. However, a number of studies showed that the beneficial effects are mediated by indirect mechanisms, such as attenuating inflammation, reducing scar thickness, enhancing autophagy, normalizing microenvironmental/metabolic profiles, releasing trophic factors and cytokines, and possibly replacing damaged cells [ 8 , 9 , 10 ]. In 2005, Bang and colleagues firstly transplanted autologous mesenchymal stem cell to five stroke patients and patients’ functional recovery was improved in 1 year follow-up with no cell-related adverse effect [ 11 ]. Since then, a number of clinical trials have been conducted to verify the efficacy and safety of stem cell-based therapies for ischemic stroke with different stem cell types, doses, and delivery routes at different phases of stroke [ 12 ]. But the outcomes in different stroke scales are inconsistent [ 13 , 14 ]. In this study, we attempted to investigate the effectiveness and safety of stem cell-based therapies for ischemic stroke.

Our review was registered on PROSPERO, the international prospective register of systematic reviews ( http://www.crd.york.ac.uk/PROSPERO ), registration number CRD42019135805. The PRISMA checklist is available in Additional file  1 .

Inclusion criteria and exclusion criteria

The inclusion criteria for the studies were (1) patients with ischemic stroke confirmed by computerized tomography or magnetic resonance imaging scan regardless of the disease phase; (2) interventions involved stem cell-based therapies, regardless of stem cell types and the delivery routes; (3) comparison involved standard treatment for the management of stroke, injection of placebo or no treatment; and (4) efficacy outcomes (measured by National Institutes of Health Stroke Scale (NIHSS), modified Rankin scale (mRS), or Barthel index (BI)) and safety outcomes (including death and other adverse effects) were reported. Exclusion criteria were (1) patients aged over 80 years, (2) single-arm studies, or (3) outcome data could not be extracted.

Search strategy

Two independent observers (M.T. and X.D.) searched the following electronic bibliographic databases: PubMed, EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials), and Web of Science (Science Citation Index Expanded) from inception to May 31, 2019. The keywords used in the search strategy included “stem cells,” “cell therapy,” “stroke,” “cell transplantation,” and “brain infarction.” The search strategy for PubMed is available in Additional file  2 . The search terms were adapted for use with other databases in combination with database-specific filters for clinical trials, where these were available. There was no language restriction. The search was re-run on Jan 20, 2020, just before the final analysis, and further studies were retrieved for inclusion, and there was no additional included study.

Selection of studies

Titles and/or abstracts of all relevant studies were screened independently by two reviewers (K.W. and L.L.) to identify studies that met the above inclusion criteria. The full text of these potentially eligible studies was retrieved and independently assessed for eligibility by two review team members. Any disagreement between the two reviewers regarding the eligibility of a study was resolved through discussion with a third reviewer (C.L.).

Data extraction

A standardized, pre-piloted form was used to extract data from the included studies for assessment of study quality and evidence synthesis. Extracted information included country in which the study was conducted, study population and participant demographics, details of the intervention and control conditions, outcomes and times of measurement, and information for the assessment of the risk of bias. Two reviewers (X.D. and M.T.) extracted data independently; discrepancies were identified and resolved through discussion (with a third reviewer (Zh.L.) when necessary). Missing data were requested from study authors.

Quality of assessment

Assessment of the quality of the included studies was performed using the method recommended by Cochrane Handbook for Systematic Reviews of Interventions [ 15 ]. For randomized controlled trial (RCT), the Cochrane risk of bias tool was used. This method comprised assessments of the risk (low risk, high risk, or unclear risk) of potential bias in seven domains: random sequence generation, allocation concealment, blinding of outcome assessment, blinding of participants and personnel, incomplete outcome data, selective reporting, and other biases, such as the baseline, source of funding, and academic biases. For non-randomized study (NRS), the Newcastle-Ottawa Scale was used [ 16 ]. This method comprised assessments of the risk of potential bias in three domains: selection, comparability, and outcome. Study ratings of seven to nine stars corresponded to high quality, five to six stars to moderate quality, and four stars or less to low quality. Two reviewers (C.L. and X.D.) independently assessed the quality of the included trials. Disagreements between the reviewers over the risk of bias were resolved by discussion with a third reviewer (Zh.L.).

Statistical analysis

We provided summaries of intervention effects for each study by calculating risk ratios (for dichotomous outcomes) or mean differences (for continuous outcomes). For studies that used the same type of intervention and comparator, with the same outcome measure, we pooled the results using a random effect meta-analysis, with mean differences (MD) for continuous outcomes and risk ratios (RR) for binary outcomes, and calculated 95% confidence intervals (CI) and two-sided P value for each outcome. Studies in different types (RCT or NRS) were pooled separately. Heterogeneity between the studies was assessed using both of the chi-square test and the I 2 statistic, and in the I 2 value, more than 50% were considered to represent substantial heterogeneity. We conducted sensitivity analyses based on study quality. We used stratified meta-analyses to explore heterogeneity in effect estimates according to study quality, study populations, the logistics of intervention provision, and intervention content. Review Manager 5.3 software was used for statistical analysis.

Results of the search

A total of 3791 records were identified and no additional record. One thousand One hundred eighty-three records were excluded as duplicates. An additional 2476 references were excluded because they were not relevant. After full-text review of the remaining 132 references, referring to 71 studies, we excluded 31 ongoing studies and 24 single-arm studies (Additional file 2 ). Finally, we included 16 studies [ 11 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ] involving 740 participants in this review (Fig.  1 ).

figure 1

Flow diagram of this meta-analysis according to PRISMA 2009

Characteristics of included studies

Of the sixteen studies, nine were RCTs and seven were NRSs, fifteen were written in English and one was written in Chinese. Most of the studies were in Asia: six in India, three in China, and two in South Korea. Most of the studies included patients with NIHSS more than 4, involving the middle cerebral artery territory, and with at least 8 weeks of follow-up. All studies used adult human non-neural stem cells: five bone marrow-derived mesenchymal cells (MSCs), six bone marrow-derived mononuclear cells (BMMNCs), one peripheral blood stem cells (PBSCs), one multipotent adult progenitor cells (MultiStem), one aldehyde dehydrogenase cells (ALD-401), one both endothelial progenitor cells (EPCs) and MSCs, and one both MSCs and BMMNCs. The most used administration route was intravenous injection. All studies reported efficacy outcomes and safety outcomes. The characteristics of the included studies are shown in Table  1 .

Risk of bias in included studies

For RCTs [ 11 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ], the Cochrane risk of bias tool was used. Seven RCTs mentioned “random” and described the method of generating a random sequence. Due to the procedures of stem cell transplantation (i.e., bone marrow aspiration or stereotaxic intracerebral implantation), five RCTs were blinded only to outcome assessors and not to participants. Eight RCTs reported that the loss of follow-up was less than 20%. In four RCTs, primary outcomes listed in published protocols were adequately reported in the results. We did not identify any other potential sources of bias in eight RCTs. The detailed assessments are shown in Fig.  2 .

figure 2

Risk of bias item presented as percentages across all included RCTs

For NRSs [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ], the Newcastle-Ottawa Scale was used. For selection, all the studies were given two stars. For comparability, four studies were given two stars and three studies were given one star. For outcome, six studies were given three stars and one study was given two stars. The overall quality of NRSs was moderate in 5 studies and high in 2 studies (Table  2 ).

Efficacy outcomes

Eight RCTs [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ] and two NRSs [ 29 , 31 ] reported the mRS at the end of follow-up (ranged from 6 months to 7 years). But in one RCT [ 24 ], the mRS could not be extracted and the corresponding author did not reply to our email inquiries. Participants in the stem cell group had a trend beneficial effect in RCTs (MD − 0.41, 95% CI − 0.82 to − 0.00, I 2  = 67%, Fig.  3 a), but not in NRSs (MD − 0.81, 95% CI − 0.68 to 0.32, I 2  = 0%, Fig.  3 b).

figure 3

Forest plot of mRS comparing the stem cell group and the control group for RCTs and NRSs. a Participants in the stem cell group had a trend beneficial effect in RCTs (MD − 0.41, 95% CI − 0.82 to − 0.00, I 2  = 67%). b Participants in stem cell group had no beneficial effect in NRSs (MD − 0.81, 95% CI − 0.68 to 0.32, I 2  = 0%)

Seven RCTs [ 17 , 18 , 19 , 20 , 21 , 23 , 24 ] and one NRS [ 29 ] reported the NIHSS at the end of follow-up (ranged from 6 months to 4 years). But in one RCT [ 24 ], the data of NIHSS could not be extracted and the corresponding author did not reply to our email inquiries. Compared with controls, participants in the stem cell group had a significantly better outcome in RCTs (MD − 1.63, 95% CI − 2.73 to − 0.53, I 2  = 60%, Fig.  4 a), but not in NRS (MD − 0.90, 95% CI − 2.90 to 1.10, Fig.  4 b).

figure 4

Forest plot of NIHSS comparing the stem cell group and control group for RCTs and NRSs. a Participants in the stem cell group had a significantly better outcome compared with controls in RCTs (MD − 1.63, 95% CI − 2.73 to − 0.53, I 2  = 60%). b Participants in the stem cell group had no beneficial effect in NRSs (MD − 0.90, 95% CI − 2.90 to 1.10, b )

Five RCTs [ 11 , 19 , 21 , 23 , 24 ] and five NRSs [ 25 , 26 , 27 , 28 , 29 ] reported the BI at the end of follow-up (ranged from 8 weeks to 7 years). But in one RCT [ 24 ], the data of BI could not be extracted and the corresponding author did not reply to our email inquiries. The stem cell group had a larger effect size than the control group in both RCTs (MD 14.68, 95% CI 1.12 to 28.24, I 2  = 68%, Fig.  5 a) and NRSs (MD 6.40, 95% CI 3.14 to 9.65, I 2  = 0%, Fig.  5 b).

figure 5

Forest plot of BI comparing the stem cell group and control group for RCTs and NRSs. a Stem cell group had a larger effect size than control group in RCTs (MD 14.68, 95% CI 1.12 to 28.24, I 2  = 68%). b The stem cell group had a larger effect size than the control group in NRSs (MD 6.40, 95% CI 3.14 to 9.65, I 2  = 0%)

Safety outcomes

Eight RCTs [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ] and seven NRSs [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ] reported death at the end of follow-up (ranged from 8 weeks to 7 years). There was no significant difference between the stem cell and control group in RCTs (RR 0.60, 95% CI 0.35 to 1.03, I 2  = 4%, Fig.  6 a) and NRSs (RR 2.59, 95% CI 0.11 to 59.93, Fig.  6 b).

figure 6

Forest plot of death comparing stem cell group and control group for RCTs and NRSs. a There was no significant difference between the stem cell and control group in RCTs (RR 0.60, 95% CI 0.35 to 1.03, I 2  = 4%). b There was no significant difference between the stem cell and control group in NRSs (RR 2.59, 95% CI 0.11 to 59.93)

Adverse effects

All RCTs and NRSs reported adverse effects at the end of follow-up (ranged from 8 weeks to 7 years). No adverse effect was reported in one RCTs and three NRSs. Fever, headache, and recurrent stroke were the most frequently reported cell-related adverse effects. Other cell-related adverse effects, such as seizures and embolisms, were reported as well. However, neoplasms, tissue overgrowth, and ectopic cell engraftment were not reported. General adverse effects, including psychological illness, renal disorders, and gastrointestinal disorders, were reported. The details of adverse effects reported in each study are shown in Table  3 .

In our review, stem cell-based therapies were related to better outcomes when measured by NIHSS and BI in RCTs and by BI in NRSs. Stem cell group had slightly better in mRS and death but without significant difference. mRS, NIHSS, and BI are widely used scales for stroke in clinical trials. mRS scores range from 0 to 6, which can assess the patient’s functional independence. NIHSS is an 11-item scale which can accurately measure the stroke-related deficits and monitor neurological changes for serial assessment. BI is a 10-item scale to observe patients in a number of key activities of daily living, which can be used to assess the change in patients with stroke [ 32 ]. Our result shows that stem cell-based therapies can improve the neurological deficits and activities of daily living in patients with ischemic stroke. But the effect is not enough to produce a significant change on a broader scale.

NIHSS is often used as an inclusion criterion in stroke trials. The inclusion criteria of the studies in our review were too broad (the NIHSS ranged from 4 to 31, Table  1 ) and the sample size was too small, which diluted the efficacy effect of the stem cell-based therapies. So it is difficult to identify which patients benefit most from the stem cell-based therapies. Most studies included patients with moderate stroke (the mean NIHSS ranged from 9.3 to 15.6, Table  1 ), but stem cell-based therapies may have uniformly good outcomes for mild stroke. Further studies with narrowing the scope of NIHSS and the suitable population are needed. What is more, patients with the same score on NIHSS may have a different score on mRS or BI. Therefore, the baseline score of mRS or BI may be different. This may have an impact on the evaluation of outcomes based on mRS or BI, especially when the included cases are limited. Only one study evaluated mRS at baseline, and there was a slight improvement on mRS in the stem cell group at the end of follow-up, but the difference was not significant compared with the control group [ 24 ]. Further studies need to expand the sample size and evaluate mRS at baseline.

Many factors can influence the effects of stem cell-based therapies in clinical practice. In our review, several cell types, including MSCs, BMMNCs, PBSCs, MultiStem, ALD-401, and EPCs, were used. Moreover, neural stem cells [ 33 ], amniotic epithelial cells [ 34 ], human adult dental pulp stem cells [ 35 ], and umbilical cord blood [ 36 ] were also used in primary clinical trials. MSCs are the most extensively investigated cell type because of their potent immunosuppressive effects by producing a multitude of paracrine factors, safety or lack of ethical issues, easy to obtain, lack of immunogenicity, and ability to differentiate into tissue-specific cell line [ 37 ]. While majority of the pre-clinical and clinical studies demonstrated significant effects, the clinical significance of these findings was still unclear due to limitations in study design and sample size [ 38 ]. Studies using other types of stem cells are limited and mostly in the primary stage; more studies are needed to compare the outcomes in different cell types. Delivery routes in our review were various, including intra-arterial infusion, intravenous infusion, subarachnoid infusion, and stereotaxic implantation. The best route of administration is still unclear. MSC are not free of safety concerns when injected intra-arterially [ 39 ]. Intravenous infusion is the minimally invasive method, easy to operate, and has few side effects, so it is widely used in clinical studies [ 40 ]. In our review, the number of cells administered in the treatments of stroke were ambiguous, ranging from several million to several billion, and administered once or twice. The smallest dose of stem cells with possible highest benefit and least toxicity is needed [ 41 ]. The time window of stem cell transplant was various as well, ranging from 24 h to 2 years covering the acute, subacute, and chronic phase of ischemic stroke. Depending on the cell source/cell type, different time windows of administration may target different mechanisms and lead to a different efficiency [ 42 ]. All the factors mentioned above can explain the high heterogeneity in the efficacy outcomes of the included studies.

A recent meta-analysis focused on preclinical studies of MSCs for ischemic stroke showed that MSCs significantly improved all functional outcomes regardless of dose, intravenously administered. MSCs showed significantly greater efficacy in improving motor outcomes. Earlier administration of MSCs before 7 days in rodents might be optimal to enhance functional recovery [ 43 ]. Cui and colleagues compared the design differences between preclinical and clinical trials, and recommended freshly harvested, autologous cells and cell transplantation in acute time windows for future clinical studies [ 44 ]. These results have important implications for further clinical translation. Further studies must take cell type, cell dose, route of cell administration, and the time window into consideration. And the large scale well-designed clinical trials should follow the guidelines organized by researchers in the academia, industry leaders, and regulatory representatives [ 45 , 46 , 47 , 48 , 49 ]. At the same time, the economic value of stem cell-based therapies in the treatment of ischemic stroke should be evaluated [ 50 ]. In addition, systematic analyses of clinical trial results usually focus on the functional recovery rather than infarct volume in preclinical studies. Further preclinical studies should select appropriate functional tests for the respective stroke model, species, scenario, and study duration [ 49 ].

Previous studies summarized adverse events that had been discovered in preclinical and clinical investigations assessing cell therapies for stroke [ 51 ]. Fever, headache, and stroke recurrence were frequently reported cell-related adverse effects in our review. But there was no significant difference compared with the control group according to previous results [ 13 , 14 ]. Antithrombotic treatment can reduce the risk of recurrent stroke, but only four RCTs and one NRSs reported antithrombotic treatment. The irregular use of antithrombotic treatment may be the cause of the high recurrent of stroke. For patients with symptomatic intracranial atherosclerotic disease, aggressive medical therapy is needed [ 52 ]. Rehabilitation can reduce the risk of adverse effects such as medical morbidity and psychological illness [ 53 ]. But only three RCTs and five NRSs in our review reported rehabilitation therapies. What is more, mind-body movements such as yoga and tai chi are useful alternative rehabilitation measures [ 54 , 55 ]. Further stem cell studies need to take standardized medical and rehabilitation therapies into account, because those may reduce the risk of adverse effects.

Extensive attempts have been made to improve the efficacy of stem cell-based therapies for ischemic stroke and reduce the risk of adverse effects recently. Strategies to enhance the endurance and efficacy of grafted stem cells in ischemic conditions include treating with growth factors, pharmacological agents, ischemia/hypoxia, or electrical stimulation and have increased paracrine potentials [ 56 , 57 , 58 ]. Stem cells modified with exogenous growth factor genes such as vascular endothelial growth factor; brain-derived neurotrophic factor by viral or non-viral delivery system can significantly increase the paracrine effects and decrease the mortality of mice [ 59 , 60 ]. Implantation of modified bone marrow-derived mesenchymal stem cells (SB623) transiently transfected with the human Notch-1 intracellular domain in a patient with stable chronic stroke is safe and is accompanied by improvements in clinical outcomes [ 61 ]. It is now well established that there is no engraftment of MSCs in the brain after intravenous administration and the recovery effects observed in some ischemic animal models are mediated by factors secreted by MSCs [ 62 ]. Recently, extracellular vesicles released by MSCs or NSCs are recognized as effective in vivo. Compared to stem cells, they have similar effects but with lower risk (in terms of vessel occlusion) [ 63 , 64 ]. Extracellular vesicles are emerging as a novel alternative to cell therapy [ 65 ].

Our review has several limitations. Clinical trials of stem cell-based therapies for ischemic stroke are still in early stage. The number of cases in the stem cell group was less than thirty in most included studies. There was high heterogeneity in the efficacy outcomes of RCTs. Many factors such as cell types, cell numbers, delivery routes, time window, and medical and rehabilitation therapies affect the efficacy of stem cells. The explorations of the sensitivity and heterogeneity were not feasible owing to the small number of included studies. We failed to extract the efficacy outcomes of a recent RCT because the outcome indicators were unclear and the author was not contacted.

In our review, stem cell-based therapies can improve the neurological deficits and activities of daily living in patients with ischemic stroke, but the benefits are still limited. At present, the clinical trial of stem cell-based therapies for ischemic stroke is still in the early stage, and participants are still limited. Further clinical trials are needed to find out the suitable population and explore the best option of stem cell-based therapy for ischemic stroke.

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Abbreviations

Aldehyde dehydrogenase

Barthel index

Bone marrow-derived mononuclear cell

European Stroke Scale

ESS Motor Subscale

Endothelial progenitor cell

European Quality of Life

Functional independence measure

Intra-arterial infusion

Internal carotid artery

Intravenous infusion

Middle cerebral artery

Medical Research Council

Mesenchymal stem cell

Modified Rankin scale

National Institute of Health stroke scale

Peripheral blood stem cell

Scandinavian Stroke Scale

Confidence interval

Mean difference

Non-randomized study

Randomized controlled trial

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Acknowledgements

This study was supported by a grant from China-Japan Friendship Hospital Youth Science and Technology Excellence Project (No. 2014-QNYC-A-04).

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Zh.L., Z.L., and J.L. designed the systematic review. M.T. and X.D. did the literature search. C.L., K.W., and L.L. reviewed all the publications. Zh.L., X.D., and M.T. extracted the information and data from the included studies. Zh.L., C.L., and X.D. did the data analysis and produced the figures and tables. Zh.L., K.W., and X.D. wrote the paper. Z.L. and J.L. revised the manuscript; Zh.L. and X.D. contributed equally to this work. All authors have read and agreed to the published version of the manuscript.

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Li, Z., Dong, X., Tian, M. et al. Stem cell-based therapies for ischemic stroke: a systematic review and meta-analysis of clinical trials. Stem Cell Res Ther 11 , 252 (2020). https://doi.org/10.1186/s13287-020-01762-z

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The promise and potential of stem cells in Parkinson’s disease

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Neurosurgeon Viviane Tabar has scrubbed in. In front of her is the first participant in a clinical trial to determine whether stem cells can be safely injected into the brains of people with Parkinson’s disease. The cells had been frozen, but they are now thawed and sitting on ice, waiting for their moment.

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Stem Cell Therapy: a Look at Current Research, Regulations, and Remaining Hurdles

Stem cell therapies offer great promise for a wide range of diseases and conditions. However, stem cell research—particularly human embryonic stem cell research—has also been a source of ongoing ethical, religious, and political controversy.

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In September 2014, the Sanford Stem Cell Clinical Center at the University of California, San Diego (UCSD) Health System announced the launch of a groundbreaking clinical trial to assess the safety of neural stem cell–based therapy in patients with chronic spinal cord injury. Researchers hope that the transplanted stem cells will develop into new neurons that replace severed or lost nerve connections and restore at least some motor and sensory function. 1

Two additional clinical trials at UCSD are testing stem cell–derived therapy for type-1 diabetes and chronic lymphocytic leukemia, the most common form of blood cancer. 1

These three studies are significant in that they are among the first efforts in stem cell research to make the leap from laboratory to human clinical trials. While the number of patients involved in each study is small, researchers are optimistic that as these trials progress and additional trials are launched, a greater number of patients will be enrolled. UCSD reports that trials for heart failure, amyotrophic lateral sclerosis, and blindness are in planning stages. 1

The study of stem cells offers great promise for better understanding basic mechanisms of human development, as well as the hope of harnessing these cells to treat a wide range of diseases and conditions. 2 However, stem cell research— particularly human embryonic stem cell (hESC) research, which involves the destruction of days-old embryos—has also been a source of ongoing ethical, religious, and political controversy. 2

The Politics of Progress

In 1973, the Department of Health, Education, and Welfare (now the Department of Health and Human Services) placed a moratorium on federally funded research using live human embryos. 3 , 4 In 1974, Congress adopted a similar moratorium, explicitly including in the ban embryos created through in vitro fertilization (IVF). In 1992, President George H.W. Bush vetoed legislation to lift the ban, and in 2001, President George W. Bush issued an executive order banning federal funding on stem cells created after that time. 3 , 4 Some states, however, have permitted their limited use. New Jersey, for example, allows the harvesting of stem cells from cloned human embryos, whereas several other states prohibit the creation or destruction of any human embryos for medical research. 3 , 4

In 2009, shortly after taking office, President Barack Obama lifted the eight-year-old ban on federally funded stem cell research, allowing scientists to begin using existing stem cell lines produced from embryos left over after IVF procedures. 5 (A stem cell line is a group of identical stem cells that can be grown and multiplied indefinitely.)

The National Institutes of Health (NIH) Human Embryonic Stem Cell Registry 6 lists the hESCs eligible for use in NIH-funded research. At this writing, 283 eligible lines met the NIH’s strict ethical guidelines for human stem cell research pertaining to the embryo donation process. 7 For instance, to get a human embryonic stem cell line approved, grant applicants must show that the embryos were “donated by individuals who sought reproductive treatment and who gave voluntary written consent for the human embryos to be used for research purposes.” 8 The ESCs used in research are not derived from eggs fertilized in a woman’s body. 9

Because of the separate legislative ban, it is still not possible for researchers to create new hESC lines from viable embryos using federal funds. Federal money may, however, be used to research lines that were derived using private or state sources of funding. 5

While funding restrictions and political debates may have slowed the course of stem cell research in the United States, 10 the field continues to evolve. This is evidenced by the large number of studies published each year in scientific journals on a wide range of potential uses across a variety of therapeutic areas. 11 – 13

The Food and Drug Administration (FDA) has approved numerous stem cell–based treatments for clinical trials. A 2013 report from the Pharmaceutical Research and Manufacturers of America lists 69 cell therapies as having clinical trials under review with the FDA, including 15 in phase 3 trials. The therapeutic categories represented in these trials include cardiovascular disease, skin diseases, cancer and related conditions, digestive disorders, transplantation, genetic disorders, musculoskeletal disorders, and eye conditions, among others. 14

Still, the earliest stem cell therapies are likely years away. To date, the only stem cell–based treatment approved by the FDA for use in this country is for bone marrow transplantation. 15 As of 2010 (the latest year for which data are available), more than 17,000 blood cancer patients had had successful stem cell transplants. 16

A Brief Stem Cell Timeline

Research on stem cells began in the late 19th century in Europe. German biologist Ernst Haeckel coined the term stem cell to describe the fertilized egg that becomes an organism. 17

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In the U.S., the study of adult stem cells took off in the 1950s when Leroy C. Stevens, a cancer researcher based in Bar Harbor, Maine, found large tumors in the scrotums of mice that contained mixtures of differentiated and undifferentiated cells, including hair, bone, intestinal, and blood tissue. Stevens and his team concluded that the cells were pluripotent, meaning they could differentiate into any cell found in a fully grown animal. Stem cell scientists are using that carefully documented research today. 17

In 1968, Robert A. Good, MD, PhD, at the University of Minnesota, performed the first successful bone marrow transplant on a child suffering from an immune deficiency. Scientists subsequently discovered how to derive ESCs from mouse embryos and in 1998 developed a method to take stem cells from a human embryo and grow them in a laboratory. 17

Why Stem Cells?

Many degenerative and currently untreatable diseases in humans arise from the loss or malfunction of specific cell types in the body. 9 While donated organs and tissues are often used to replace damaged or dysfunctional ones, the supply of donors does not meet the clinical demand. 18 Stem cells seemingly provide a renewable source of replacement cells and tissues for transplantation and the potential to treat a myriad of conditions.

Stem cells have two important and unique characteristics: First, they are unspecialized and capable of renewing themselves through cell division. When a stem cell divides, each new cell has the potential either to remain a stem cell or to differentiate into other kinds of cells that form the body’s tissues and organs. Stem cells can theoretically divide without limit to replenish other cells that have been damaged. 9

Second, under certain controlled conditions, stem cells can be induced to become tissue- or organ-specific cells with special functions. They can then be used to treat diseases affecting those specific organs and tissues. While bone marrow and gut stem cells divide continuously throughout life, stem cells in the pancreas and heart divide only under appropriate conditions. 9

Embryonic Versus Adult Stem Cells

There are two main types of stem cells: 1) embryonic stem cells (ESCs), found in the embryo at very early stages of development; and 2) somatic or adult stem cells (ASCs), found in specific tissues throughout the body after development. 9

The advantage of embryonic stem cells is that they are pluripotent—they can develop into any of the more than 200 cell types found in the body, providing the potential for a broad range of therapeutic applications. Adult stem cells, on the other hand, are thought to be limited to differentiating into different cell types of their tissue of origin. 9 Blood cells, for instance, which come from adult stem cells in the bone marrow, can specialize into red blood cells, but they will not become other cells, such as neurons or liver cells.

A significant advantage of adult stem cells is that they offer the potential for autologous stem cell donation. In autologous transplants, recipients receive their own stem cells, reducing the risk of immune rejection and complications. Additionally, ASCs are relatively free of the ethical issues associated with embryonic stem cells and have become widely used in research.

Induced Pluripotent Stem Cells

Representing a relatively new area of research, induced pluripotent stem cells (iPSCs) are adult stem cells that have been genetically reprogrammed back to an embryonic stem cell–like state. The reprogrammed cells function similarly to ESCs, with the ability to differentiate into any cell of the body and to create an unlimited source of cells. So iPSCs have significant implications for disease research and drug development.

Pioneered by Japanese researchers in 2006, iPSC technology involves forcing an adult cell, such as a skin, liver, or stomach cell, to express proteins that are essential to the embryonic stem cell identity. The iPSC technology not only bypasses the need for human embryos, avoiding ethical objections, but also allows for the generation of pluripotent cells that are genetically identical to the patient’s. Like adult cells, these unlimited supplies of autologous cells could be used to generate transplants without the risk of immune rejection. 9

In 2013, researchers at the Spanish National Cancer Research Centre in Madrid successfully reprogrammed adult cells in mice, creating stem cells that can grow into any tissue in the body. Prior to this study, iPSCs had never been grown outside Petri dishes in laboratories. 19 And, in July 2013, Japan’s health minister approved the first use of iPSCs in human trials. The Riken Center for Developmental Biology will use the cells to attempt to treat age-related macular degeneration, a common cause of blindness in older people. The small-scale pilot study would test the safety of iPSCs transplanted into patients’ eyes. 20

The Promise of iPSCs

According to David Owens, PhD, Program Director of the Neuroscience Center at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), one of the fundamental hurdles to using stem cells to treat disease is that scientists do not yet fully understand the diseases themselves, that is, the genetic and molecular signals that direct the abnormal cell division and differentiation that cause a particular condition. “You want that before you propose a therapeutic,” he says, “because you want a firm, rational basis for what you’re trying to do, what you’re trying to change.”

Although most of the media attention around stem cells has focused on regenerative medicine and cell therapy, researchers are finding that iPSCs, in particular, hold significant promise as tools for disease modeling. 21 , 22 A major barrier to research is often inaccessibility of diseased tissue for study. 23 Because iPSCs can be derived directly from patients with a given disease, they display all of the molecular characteristics associated with the disease, thereby serving as useful models for the study of pathological mechanisms.

“The biggest payoff early on will be using these cells as a tool to understand the disease better,” says Dr. Owens. For instance, he explains that creating dopamine neurons from iPSC lines could help scientists more closely study the mechanisms behind Parkinson’s disease. “If we get a better handle on the disorders themselves, then that will also help us generate new therapeutic targets.” Recent studies show the use of these patient-specific cells to model other neurodegenerative disorders, including Alzheimer’s and Huntington’s diseases. 24 – 26

In addition to using iPSC technology, it is also possible to derive patient-specific stem cell lines using an approach called somatic cell nuclear transfer (SCNT). This process involves adding the nuclei of adult skin cells to unfertilized donor oocytes. As reported in spring 2014, a team of scientists from the New York Stem Cell Foundation Research Institute and Columbia University Medical Center used SCNT to create the first disease-specific embryonic stem cell line from a patient with type-1 diabetes. The insulin-producing cells have two sets of chromosomes (the normal number in humans) and could potentially be used to develop personalized cell therapies. 27

Many Hurdles Ahead

The development of iPSCs and related technologies may help address the ethical concerns and open up new possibilities for studying and treating disease, but there are still barriers to overcome. One major obstacle is the tendency of iPSCs to form tumors in vivo . Using viruses to genomically alter the cells can trigger the expression of cancer-causing genes, or oncogenes. 28

Much more research is needed to understand the full nature and potential of stem cells as future medical therapies. It is not known, for example, how many kinds of adult stem cells exist or how they evolve and are maintained. 9

Some of the challenges are technical, Dr. Owens explains. For instance, generating large enough numbers of a cell type to provide the amounts needed for treatment is difficult. Some adult stem cells have a very limited ability to divide, making it difficult to multiply them in large numbers. Embryonic stem cells grow more quickly and easily in the laboratory. This is an important distinction because stem cell replacement therapies require large numbers of cells. 29

Also, says Dr. Owens, stem cell transplants present immunological hurdles: “If you do introduce cells into a tissue, will they be rejected if they’re not autologous cells? Or, you might have immunosuppression with the individual who received the cells, and then there are additional complications involved with that. That’s still not entirely clear.”

Such safety issues need to be addressed before any new stem cell–based therapy can advance to clinical trials with real patients. According to Dr. Owens, the preclinical testing stage typically takes about five years. This would include assessment of toxicity, tumorigenicity, and immunogenicity of the cells in treating animal models for disease. 30

“Those are things we have to continually learn about and try to address. It will take time to understand them better,” Dr. Owens says. Asked about the importance of collaboration in overcoming the scientific, regulatory, and financial challenges that lie ahead, he says, “It’s unlikely that one entity could do it all alone. Collaboration is essential.”

Research and Clinical Trials

Ultimately, stem cells have huge therapeutic potential, and numerous studies are in progress at academic institutions and biotechnology companies around the country. Studies at the NIH span multiple disciplines, notes Dr. Owens, who oversees funding for stem cell research at NINDS. ( Figure 1 shows the recent history of NIH funding for stem cell research.) He describes one area of considerable interest as the promotion of regeneration in the brain based on endogenous stem cells. Until recently, it was believed that adult brain cells could not be replaced. However, the discovery of neurogenesis in bird brains in the 1980s led to startling evidence of neural stem cells in the human brain, raising new possibilities for treating neurodegenerative disorders and spinal cord injuries. 31

“It’s a fascinating idea,” says Dr. Owens. “It’s unclear still what the functions of those cells are. They could probably play different roles in different species, but just the fundamental properties themselves are very interesting.” He cites a number of NINDS-funded studies looking at those basic properties.

In another NIH-funded study, Advanced Cell Technology (ACT), a Massachusetts-based biotechnology company, is testing the safety of hESC-derived retinal cells to treat patients with an eye disease called Stargardt’s macular dystrophy. A second ACT trial is testing the safety of hESC-derived retinal cells to treat age-related macular degeneration patients. 32 , 33

In April 2014, scientists at the University of Washington reported that they had successfully regenerated damaged heart muscles in monkeys using heart cells created from hESCs. The research, published in the journal Nature , was the first to show that hESCs can fully integrate into normal heart tissue. 34

The study did not answer every question and had its complications—it failed to show whether the transplanted cells improved the function of the monkeys’ hearts, and some of the monkeys developed arrhythmias. 34 , 35 Still, the researchers are optimistic that it will pave the way for a human trial before the end of the decade and lead to significant advances in treating heart disease. 29

In May 2014, Asterias Biotherapeutics, a California-based biotechnology company focused on regenerative medicine, announced the results of a phase 1 clinical trial assessing the safety of its product AST-OPC1 in patients with spinal cord injuries. 36 The study represents the first-in-human trial of a cell therapy derived from hESCs. Results show that all five subjects have had no serious adverse events associated with the administration of the cells, with the AST-OPC1 itself, or with the immunosuppressive regimen. A phase 1/2a dose-escalation study of AST-OPC1 in patients with spinal cord injuries is awaiting approval from the FDA. 37

The FDA itself has a team of scientists studying the potential of mesenchymal stem cells (MSCs), adult stem cells traditionally found in the bone marrow. Multipotent stem cells, MSCs differentiate to form cartilage, bone, and fat and could be used to repair, replace, restore, or regenerate cells, including those needed for heart and bone repair. 38

Publicly available information about federally and privately funded clinical research studies involving stem cells can be found at http://clinicaltrials.gov . However, the FDA cautions that the information provided on that site is supplied by the product sponsors and is not reviewed or confirmed by the agency.

“The biggest payoff early on will be using these cells as a tool to understand the disease better. If we get a better handle on the disorders themselves, then that will also help us generate new therapeutic targets.” —David Owens, PhD, Program Director, Neuroscience Center, National Institute of Neurological Disorders and Stroke

Global Research Efforts

Stem cell research policy varies significantly throughout the world as countries grapple with the scientific and social implications. In the European Union, for instance, stem cell research using the human embryo is permitted in Belgium, Britain, Denmark, Finland, Greece, the Netherlands, and Sweden; however, it is illegal in Austria, Germany, Ireland, Italy, and Portugal. 39

In those countries where cell lines are accessible, research continues to create an array of scientific advances and widen the scope of stem cell application in human diseases, disorders, and injuries. For example, in February 2014, Cellular Biomedicine Group, a China-based company, released the six-month follow-up data analysis of its phase 1/2a clinical trial for ReJoin, a human adipose-derived mesenchymal precursor cell (haMPC) therapy for knee osteoarthritis. The study, which tested the safety and efficacy of intra-articular injections of autologous haMPCs to reduce inflammation and repair damaged joint cartilage, showed knee pain was significantly reduced and knee mobility was improved. 40 And the journal Stem Cell Research & Therapy reported that researchers at the University of Adelaide in Australia recently completed a project showing stem cells taken from teeth could form “complex networks of brain-like cells.” Although the cells did not grow into full neurons, the researchers say that it will happen given time and the right conditions. 41

The Regulation of Stem Cells

In February 2014, the U.S. Court of Appeals for the District of Columbia Circuit upheld a 2012 ruling that a patient’s stem cells for therapeutic use fall under the aegis of the FDA. 42 The appeals case involved the company Regenerative Sciences, which was using patients’ MSCs in its Regenexx procedure to treat orthopedic problems. 43

The FDA’s Center for Biologics Evaluation and Research (CBER) regulates human cells, tissues, and cellular and tissue-based products (HCT/P) intended for implantation, transplantation, infusion, or transfer into a human recipient, including hematopoietic stem cells. Under the authority of Section 361 of the Public Health Service Act, the FDA has established regulations for all HCT/Ps to prevent the transmission of communicable diseases. 44

The Regenexx case highlights an ongoing debate about whether autologous MSCs are biological drugs subject to FDA approval or simply human cellular and tissue products. Some medical centers collect, concentrate, and reinject MSCs into a patient to treat osteoarthritis but do not add other agents to the injection. The FDA contends that any process that includes culturing, expansion, and added growth factors or antibiotics requires regulation because the process constitutes significant manipulation. Regenerexx has countered that the process does not involve the development of a new drug, which could be given to a number of patients, but rather a patient’s own MSCs, which affects just that one patient.

Ensuring the safety and efficacy of stem cell–based products is a major challenge, says the FDA. Cells manufactured in large quantities outside their natural environment in the human body can potentially become ineffective or dangerous and produce significant adverse effects such as tumors, severe immune reactions, or growth of unwanted tissue. Even stem cells isolated from a person’s own tissue can potentially present these risks when put into an area of the body where they could not perform the same biological function that they were originally performing. Stem cells are immensely complex, the FDA cautions—far more so than many other FDA-regulated products—and they bring with them unique considerations for meeting regulatory standards.

To date, no U.S. companies have received FDA approval for any autologous MSC therapy, although a study is ongoing to assess the feasibility and safety of autologous MSCs for osteoarthritis. 45 One of the major risks with MSCs is that they could potentially lead to cancer or differentiation into bone or cartilage. 46

What’s Next

The numerous stem cell studies in progress across the globe are only a first step on the long road toward eventual therapies for degenerative and life-ending diseases. Because of their unlimited ability to self-renew and to differentiate, embryonic stem cells remain, theoretically, a potential source for regenerative medicine and tissue replacement after injury or disease. However, the difficulty of producing large quantities of stem cells and their tendency to form tumors when transplanted are just a few of the formidable hurdles that researchers still face. In the meantime, the shorter-term payoff of using these cells as a tool to better understand diseases has significant implications.

Social and ethical issues around the use of embryonic stem cells must also be addressed. Many nations, including the U.S., have government-imposed restrictions on either embryonic stem cell research or the production of new embryonic stem cell lines. Induced pluripotent stem cells offer new opportunities for development of cell-based therapies while also providing a way around the ethical dilemma of using embryos, but just how good an alternative they are to embryonic cells remains to be seen.

It is clear that many challenges must be overcome before stem cells can be safely, effectively, and routinely used in the clinical setting. However, their potential benefits are numerous and hold tremendous promise for an array of new therapies and treatments.

Acknowledgments

The authors wish to thank the FDA staff for their support in writing this article and Rachael Conklin, Consumer Safety Officer, Consumer Affairs Branch, Division of Communication and Consumer Affairs, Center for Biologics Evaluation and Research, for her help in organizing the comments provided by FDA staff.

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FDA Approves First Cellular Therapy to Treat Patients with Unresectable or Metastatic Melanoma

FDA News Release

Today, the U.S. Food and Drug Administration approved Amtagvi (lifileucel), the first cellular therapy indicated for the treatment of adult patients with a type of skin cancer (melanoma) that is unable to be removed with surgery (unresectable) or has spread to other parts of the body (metastatic) that previously has been treated with other therapies (a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor). 

“Unresectable or metastatic melanoma is an aggressive form of cancer that can be fatal,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “The approval of Amtagvi represents the culmination of scientific and clinical research efforts leading to a novel T cell immunotherapy for patients with limited treatment options.”

Melanoma is a form of skin cancer that is often caused by exposure to ultraviolet light, which can come from sunlight or indoor tanning. Although melanomas only represent approximately 1% of all skin cancers, they account for a significant number of cancer-related deaths. Melanoma can spread to other parts of the body if not detected and treated early, resulting in metastatic disease. 

Treatment for unresectable or metastatic melanoma may include immunotherapy using PD-1 inhibitors, which are antibodies targeting certain proteins in the body to help the immune system fight off cancer cells. In addition, drugs targeting the BRAF gene, which helps with managing the growth and functioning of cells, may be used for treating melanoma associated with BRAF gene mutations. Those patients whose melanoma has progressed with these therapies have a high unmet medical need.

Amtagvi is a tumor-derived autologous T cell immunotherapy composed of a patient’s own T cells, a type of cell that helps the immune system fight cancer. A portion of the patient’s tumor tissue is removed during a surgical procedure prior to treatment. The patients’ T cells are separated from the tumor tissue, further manufactured and then returned to the same patient as a single dose for infusion. This is the first FDA-approved tumor-derived T cell immunotherapy.

“Melanoma is a life-threatening cancer that can cause devastating impacts to affected individuals, with a significant risk of metastasizing and spreading to other areas in the body,” said Nicole Verdun, M.D., director of the Office of Therapeutic Products in CBER. “Today’s approval reflects the FDA’s dedication and commitment to the development of innovative, safe and effective treatment options for cancer patients.”

Amtagvi was approved through the Accelerated Approval pathway , under which the FDA may approve drugs for serious or life-threatening illnesses or conditions where there is an unmet medical need and the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients (improving how patients feel or function, or whether they survive longer). This pathway generally gives patients the opportunity for earlier access to a promising therapy while the company conducts further trials to verify the predicted clinical benefit. A confirmatory trial is ongoing to verify Amtagvi’s clinical benefit.

The safety and effectiveness of Amtagvi was evaluated in a global, multicenter, multicohort clinical study including adult patients with unresectable or metastatic melanoma who had previously been treated with at least one systemic therapy, including a PD-1 blocking antibody, and if positive for the BRAF V600 mutation, a BRAF inhibitor or BRAF inhibitor with an MEK inhibitor. Effectiveness was established based on objective response rate to treatment and duration of response (measured from the date of confirmed initial objective response to the date of progression, death from any cause, starting a new anti-cancer treatment or discontinuation from follow-up, whichever came first). Among the 73 patients treated with Amtagvi at the recommended dose, the objective response rate was 31.5%, including three (4.1%) patients with a complete response and 20 (27.4%) patients with a partial response. Among patients who were responsive to the treatment, 56.5%, 47.8% and 43.5% continued to maintain responses without tumor progression or death at six, nine and 12 months, respectively.

Patients treated with Amtagvi may exhibit prolonged severe low blood count, severe infection, cardiac disorder, or develop worsened respiratory or renal function or have fatal treatment-related complications. A Boxed Warning is included in the label containing information about these risks. Patients receiving this product should be closely monitored before and after infusion for signs and symptoms of adverse reactions. Treatment should be withheld or discontinued in the presence of these symptoms, as indicated.

The most common adverse reactions associated with Amtagvi included chills, fever, fatigue, tachycardia (abnormally fast heart rate), diarrhea, febrile neutropenia (fever associated with a low level of certain white blood cells), edema (swelling due to buildup of fluid in body tissues), rash, hypotension, hair loss, infection, hypoxia (abnormally low oxygen levels in the body) and feeling short of breath. 

Amtagvi also received Orphan Drug , Regenerative Medicine Advanced Therapy , Fast Track , and Priority Review designations. 

The FDA granted the approval of Amtagvi to Iovance Biotherapeutics Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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    Recent research reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative strategies may one day become a treatment for a wide range of vexing diseases ( 2 ). In fact, the past few years witnessed, a rather exponential advancement in clinical trials revolving around stem cell-based therapies.

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    Stem Cell Research & Therapy is the major forum for translational research into stem cell therapies. An international peer-reviewed journal, it publishes high-quality open access research articles with a special emphasis on basic, translational and clinical research into stem cell therapeutics and regenerative therapies, including animal models ...

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    Stem cells are the foundation of life and have the potential to treat various diseases and disorders. This comprehensive review covers the origins, types, and applications of stem cells in medical practice, as well as the challenges and ethical issues involved. Learn more about the current state and future prospects of stem cell research and therapy from this article.

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    Using advanced timelapse imaging techniques and genetic mouse models, the research team was able to track the fate of individual AT2s in the live breathing intact lung in response to injury. They were able to show for the first time that a large fraction of alveolar stem cells (AT2s) migrate to the site of the injury.

  15. Stem Cells in the Treatment of Disease

    Figure 1. Types of Stem Cells. The derivation of induced pluripotent stem cells (iPSCs) has revolutionized stem-cell research (see the box for a list of the abbreviations used in this...

  16. Stem cells: What they are and what they do

    By Mayo Clinic Staff You've heard about stem cells in the news, and perhaps you've wondered if they might help you or a loved one with a serious disease. You may wonder what stem cells are, how they're being used to treat disease and injury, and why they're the subject of such vigorous debate.

  17. Welcome to Stem Cell Research & Therapy

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  18. Stem cells: Therapy, controversy, and research

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  19. Stem cell-based therapy for human diseases

    Stem cell therapy is a novel therapeutic approach that utilizes the unique properties of stem cells, including self-renewal and differentiation, to regenerate damaged cells and tissues in the human body or replace these cells with new, healthy and fully functional cells by delivering exogenous cells into a patient. 7 Stem cells for cell-based th...

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  21. Evaluation of the Efficacy of Stem Cells Therapy in the ...

    Stem cell therapy for periodontal defects has shown good promise in preclinical studies. The purpose of this study was to evaluate the impact of stem cell support on the regeneration of both soft and hard tissues in periodontal treatment. PubMed, Cochrane Library, Embase, and Web of Science were searched and patients with periodontal defects who received stem cell therapy were included in this ...

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    Stroke is the second most common cause of death and disability in the world, leading to a heavy burden on patients, family, and society [].As a predominant stroke subtype, ischemic stroke constituted 69.6% among all subtypes of incident stroke according to the national epidemiological survey of stroke in China [].At present, intravenous recombinant tissue plasminogen activator and endovascular ...

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    The study of stem cells offers great promise for better understanding basic mechanisms of human development, as well as the hope of harnessing these cells to treat a wide range of diseases and conditions. 2 However, stem cell research— particularly human embryonic stem cell (hESC) research, which involves the destruction of days-old embryos—has ...

  27. FDA Approves First Cellular Therapy to Treat Patients with Unresectable

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