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Systematic Review
160 (
5
); 411-427
doi:
10.25259/ijmr_2141_23

Stem cell therapy approaches for non-malignant diseases & non-haematological diseases in India: A systematic review

, ,
1Department of Inclusive Health, CSIR-National Institute of Science Communication and Policy Research, New Delhi, India
2Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
3Department of Pediatrics, All India Institute of Medical Sciences, Patna, India

For correspondence: Dr Suman Ray, Department of Inclusive Health, CSIR-National Institute of Science Communication and Policy Research, Delhi 110 012, India e-mail: sumanitrc@gmail.com

Received: , Accepted: ,
© 2024 Indian Journal of Medical Research, published by Scientific Scholar for Director-General, Indian Council of Medical Research
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Abstract

Background & objectives

Our study aims to provide the diversity of stem cell use for non-malignant, non-haematological diseases in India through the lens of clinical trials.

Methods

A PRISMA approach was used to evaluate the safety and efficacy of stem cell use for the period 2001-2021 in India. The outcomes were measured using each disease category, types of stem cells, the origin of stem cells, safety, and efficacy.

Results

Of the 9206 studies screened, 61 studies that were relevant to stem cell use for non-malignant diseases were included for analysis. Autologous stem cells (75%) were used predominantly compared to allogenic stem cells (18.33%), followed by mixed type (6.67%). Use of bone marrow-derived stem cells (51%) was dominant, followed by melanocytes (19%), adipose (7%), haematopoietic (12%), and (11%) other types of stem cells. The study revealed 37 randomized clinical trial studies conducted in the government research hospital compared to the non-government.

Interpretation & conclusions

Maintaining the gold standard for stem cell therapy requires randomized clinical trials with large sample sizes, control groups, failures, adverse effects, etc. It is important to have a monitoring and regulation system in stem cell clinical research activities with enough preclinical data and repeated exchanges between the bench and the bedside.

Keywords

Allogeneic stem cells
autologous stem cells
clinical outcomes
efficacy
non-malignant disease
safety
stem cell therapy

The World Health Organization (WHO) has expressed serious concerns regarding the increasing incidence of non-communicable diseases (NCDs) worldwide. WHO coordinates with each country to prevent and control NCDs through their leadership. However, WHO set the 2030 Agenda for Sustainable Development Goals (SDG target 3.4) to prevent and control NCDs1 An estimated 41 million people die due to non-communicable diseases each year1. Cardiovascular diseases, cancers, respiratory diseases, and diabetes; these four groups are majorly responsible for premature death1. India is now a major hub for NCDs2. To reduce the burden of NCDs, the Indian government has implemented the National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke (NPCDCS)3. However, these efforts are limited to prevention and control, not the cure.

Stem cell therapy is an important branch of multidisciplinary regenerative medicine that primarily focuses on repairing, regenerating, or rejuvenating the body function4,5. Stem cell therapy is a new hope for individuals suffering from NCDs. This includes malignant and non-malignant diseases, and the treatment plan aims for cure. Because stem cells are defined by their uniqueness of self-renewal and differentiation, their therapeutic potential has been proven in basic research, and their utility in clinical settings is being explored. For example, the treatments of spinal cord injury, heart failure, retinal and macular degeneration, and type 1 diabetes have shown promising results as injecting stem cells at the target may help in reverting to normal functioning4-6, but large clinical trials on these are still lacking so far. However, the emergence of ‘unproven stem cell therapy’ through unauthorized clinics that claim the importance of stem cell therapy as ‘magic cells or snake oil’ has raised concern regarding the safety and efficacy of stem cell therapy7,8. Moreover, various adverse effects of stem cell injection have been noted historically9. For example, during the treatment of macular degeneration, patients lose their vision10. Thus, we need more studies on the mechanisms of action, toxicological studies, and standardization and characterization of transplanted cells11,12.

For the promotion and regulation of stem cell therapy, the Indian Council for Medical Research (ICMR) and the Department of Biotechnology (DBT) initially released the National Guidelines for Stem Cell Research and Therapy in 200713. It was subsequently modified in 2013 and 2017. The guidelines were renamed as National Guidelines for Stem Cell Research (NGSCR) in 2013 by removing the word therapy and was retained as is in 2017. The NGSCR 2017 is comprehensive and continued to emphasize on consideration of stem cell-based therapy as a drug indicated in NGSCR 201314,15. Therefore, needs to go through rigorous clinical trial procedures. This guideline also provides a list of approved indications where there is no perceived need for clinical trials, and it mainly includes nearly all haematological diseases, whether malignant or not. Additionally, more comprehensive guidelines for haematological diseases are mentioned in the National Guidelines for Hematopoietic Cell Transplantation (NGHCT) 2021, released by ICMR16. Considering stem cells as a drug in NGSCR 2017 was not effective, hence the New Drugs and Clinical Trials Rules (NDCTR), 2019 implemented. Since then legal provisions have been made available for stem cells as a drug. It is hence now necessary to check the status of stem cell therapy based on the outcome of clinical trials17.

The treatment of haematological diseases using allogeneic or autologous bone marrow/blood stem cell transplantation is already established as part of medical treatment through historical development18-21. However, stem cell treatments for non-malignant and non-haematological diseases have not yet been established, and current progress is unknown in the Indian context. Hence, the authors in this study have done a comprehensive systematic analysis to study the outcomes of the clinical trials using stem cell therapy for non-malignant diseases and non-haematological diseases in India.

Materials & Methods

A systematic review was undertaken as per the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) checklist22. This review focused on previously published studies from India. Figure 1 describes the PRISMA diagram for search strategy and study selection.

PRISMA diagram for search strategy and study selection.
Fig. 1.
PRISMA diagram for search strategy and study selection.

Search strategy

We performed systematic searches with language restriction (only English) using PubMed, Web of Science, and Scopus databases. The period chosen was between 2001 and 2021, and the search was performed on January 31, 2022. The main keywords were ‘stem cell therapy’, ‘clinical trials’ and ‘India’. These keywords and their allied keywords were used for data extraction from the above databases. For example, on the Web of Science, we used search strings as (Stem OR cell OR cells) AND (Therapy OR treatment OR cure OR intervention OR therapeutic) AND (Clinical) (Topic) and INDIA (Countries/Regions) and Article (Document Types) and English (Languages). This search string was modified for Scopus and PubMed databases.

Eligibility criteria

Research articles included were related to prospective, randomized, non-randomized controlled trials and other uncontrolled clinical trials, including single-arm trials that examined the safety and efficacy of stem cell therapy in Indian adults or mixed adult and paediatric participants. Full-text articles that were available in the chosen databases were included.

Exclusion criteria

We excluded all animal studies in the first step, and malignant diseases were excluded in the next step. Non-malignant haematological diseases were also excluded because NGSCR 2017 exempted these. Single case reports, observational studies, and single-centre experience studies were excluded.

Screening and article selection

The first and second authors independently screened the selected studies and extracted the data using a standardized form. Doubts and discrepancies were fixed by discussing with the third author.

Search results

With screening and applying exclusion criteria, 8075 articles were excluded, and the remaining 302 articles were considered for full-text selection. Of the total (n=9206) articles screened, 61 articles were included for further analysis (Fig. 1).

Articles particularly related to clinical trials, including prospective, randomized, non-randomized, and pilot studies were included. Of these, single case studies, single centre experiences, historical studies, observational studies, cancer or malignancies, and haematological diseases were all excluded. Among the 61 studies, finally five were included for further analysis recorded before, and 56 were recorded after the release of the National Guidelines for Stem Cell Research and Therapy 2007.

For the purpose of discussion, the studies were sorted on the basis of organ-specificity and disease characteristics (Table)23-83. This included: dental (1 article having 15 participants), diabetes (7 articles having 153), eye (4 articles having 24 participants), heart (9 articles having 484 participants), kidney (4 articles having 539 participants), liver (2 articles 80 participants), neurological (15 articles having 794 participants), musculoskeletal (4 articles having 156 participants) and skin (15 articles 482 participants). Table I describes the main characteristics and outcomes of stem cell therapy (SCT) use for non-malignant non-haematological diseases in India based on this systematic review analysis.

Table. Stem cell characteristics and approaches for non-malignant diseases and non-haematological diseases in India
Author name Disease Category Total sample Age (yr) Follow up (months) Purpose of study Cell origin Types of cells Outcome Side effects
U et al23, 2019 Cystic maxillofacial bony defects Dental 15 . 6 Evaluate the role of BMA in regenerating new bone Autologous Bone marrow-derived Stem Cells 1) Bone defect volume reduction was statistically significant; 2) No tooth mobility; 3) Faster wound healing .
Bhansali et al24, 2009 T2DM Diabetes 10 . 6 Efficacy of Autologous Bone Marrow–Derived Stem Cell Autologous Bone Marrow-derived Stem Cells 1) Insulin requirements reduced; 2) c-peptide stimulated 1) Self-limiting nausea; 2) Vomiting; 3) Hematoma
Vanikar et al25, 2010 T1DM Diabetes 11 13 to 43 12 Efficacy and safety of combined Mixed Adipose tissue-derived insulin-secreting mesenchymal stem cells (IS-AD-MSC) and cultured bone marrow (CBM) 1) c-peptide assay- increased gradually; 2) Insulin requirement decreased; 3) HBA2c level - decreased; 4) GAD antibodies - decrease in some and others not .
Dave et al26, 2015 T1DM Diabetes 10 8 to 45 31.71 Safety and efficacy Mixed Adipose tissue-derived MSC-differentiated insulin-secreting cells (ISC) with hematopoietic stem cells (HSC). 1) c-peptide level increased; 2) HbA1c improved; 3) Insulin requirement reduced; 4) GAD ab - positive No untoward effect
Thakkar et al27, 2015 T1DM Diabetes 20 8 to 45 12 Compare & assess - safety & efficacy Mixed Adipose-derived MSC and Bone marrow-derived HSC 1) Insulin requirement reduced; 2) HBA1c reduced; 3) GAD antibody decreased; 4) Autologous SCT improved better than allogenic SCT for C-peptide No untoward effect, morbidity (pulmonary embolism, sepsis) or mortality
Thakkar et al28, 2016 T1DM Diabetes 20 8 to 45 27+ Efficacy and safety of coinfusion Mixed Adipose tissue-derived insulin-secreting mesenchymal stem cells and bone marrow-derived hematopoietic stem cells 1) Mean GAD antibody - decreased 2) Mean insulin requirement decreased 3) absence of DKA episodes in all 4) c-peptide level - increased .
Sood et al29, 2017 T2DM Diabetes 42 30 to 70 6 To find out optimal routes for deliveryof stem cells Autologous Bone Marrow-derived Mononuclear Cells 1) C-peptide assay - difference remained statistically non-significant across all groups; 2) Insulin sensitivity indices of HOMA IR and HOMA B did not show any significant differences; 3) Decrease in Insulin dosages except for peripheral intravenous route; 4) HbA1c - non-significant change .
Bhansali et al30, 2017 T2DM Diabetes 40 30 to 60 12 Efficacy and safety of ABM-MSCs and ABM-MNCs transplantation Autologous Bone marrow-derived mesenchymal stem cells and mononuclear cells 1) Insulin requirement reduction; 2) HbA1c reduction; 3) Improvement in c-peptide response; 4) Insulin sensitivity also improved .
Sangwan et al31, 2012 Unilateral limbal stem cell deficiency Eye . . . Novel simplified technique of limbal transplantation Autologous Limbal epithelial cells Epithelialised, avascular and stable corneal surface .
Sharma et al32, 2013 Total limbal stem cell deficiency Eye 4 8 - 12 26 Clinical outcome with the phenotype of rejuvenated corneal epithelium Autologous Limbal epithelial cell (cultured) 1) Epithelial transparency increased; 2) Reduction or absence of corneal vascularization and conjunctivalization; 3) No sign of signs of recurrent LSCD; 4) ocular the surface remained stable and visual acuity improved .
Titiyal et al33, 2015 Ocular burns Eye 20 . 6 Outcomes of live-related limbal allograft (Lr-CLAL) versus cadaveric keratolimbal allograft (KLAL) in limbal stem cell deficiency (LSCD) Allogenic Limbal stem cell (live and cadaveric) Lr-CLAL shows better results than KLAL regarding vision gain and ocular surface restoration. .
Kaliki et al34, 2017 Ocular surface squamous neoplasia eye 8 . 12 Compare the surgical outcomes with and without p-SLET Autologous Limbal epithelial cells None of them developed LSCD or tumor recurrence .
Kaparthi et al35, 2008 Dilated cardiomyopathy Heart 5 20-65 . Safety and efficacy Autologous Bone marrow-derived mononuclear cells 1) Procedure was safe; 2) improved myocardial contractility and LV function .
Guhathakurta et al36, 2009 Cellular Cardiomyoplasty Heart 40 . 6 Safety of protocol Mixed Bone marrow mononuclear cells and peripheral blood-derived endothelial precursor cells Marginal improvement in myocardial function .
Prasad et al37, 2012 Stroke Heart 11 30 to 70 12 Feasibility, safety and clinical outcome Autologous Bone marrow-derived mononuclear cells 1) Study was feasible; 2) Safe - no evidence of tumour formation; 3) All scores - statistically significant .
Bhasin et al38, 2013 Stroke Heart 40 18-65 6 Safety, feasibility and efficacy Autologous Bone marrow-derived mesenchymal stem cells and mononuclear cells Only the modified Barthel Index was statistically significant .
Prasad et al39, 2014 Ischemic Stroke Heart 58 18 to 75 6 Efficacy and safety of autologous BMSCs Autologous Bone marrow-derived mononuclear cells No beneficial effect of treatment on stroke outcome .
Chullikana et al40, 2015 Acute myocardial infarction Heart 20 . 24 Safety and efficacy of intravenous administration Allogenic Bone marrow-derived mesenchymal stem cell Not significant outcomes compared with placebo 1) 39 treatment-emergent adverse events; 2) SASEs - ventricular tachycardia, pericardial effusion and AMI
Nair et al41, 2015 Acute myocardial infarction Heart 250 20-65 6 Efficacy of stem cells in the improvement of left ventricular function Autologous Bone marrow-derived mononuclear cells 1) Improvement was not significant; 2) Cell dose more than 5x10^8 shows positive impact 1) Chest pain, dyspnoea and other symptoms; 2) One died due to acute stent thrombosis with acute LV failure
Patel et al42, 2015 Ischemic heart failure or non-ischemic heart failure Heart 60 . 12 Safety and feasibility Autologous Bone marrow-derived mononuclear cells Not powered to demonstrate statistical significance 1) Elevated troponin levels; 2) Catheterization site hematomas; 3) Bleeding at the marrow aspiration site; 4) Pain at the aspiration site; 5) Congestive heart failure exacerbation requiring hospital admission; 6) Ventricular arrhythmia; 7) Hematomas at the catheterization site and elevatedserum creatinine
Bhatia et al43, 2018 Subacute Ischemic Stroke Heart . . 6 Evaluate the Safety and the efficacy of intra-arterial infusion Autologous Bone marrow-derived mononuclear cells 1) Good clinical outcomes; 2) modified Rankin Scale score also improved .
Trivedi et al44, 2002 Pediatric renal transplant Kidney 44 . 18 To achieve zero-rejection status in pediatric renal allograft recipients, Allogenic Peripheral blood stem cell 1) 100% graft survival with sustained low serum creatinine value; 2) Absence of graft vs. host disease 1) Appearance of CMV
Trivedi et al45, 2003 Renal Allograft Kidney 43 . 12 Tolerance in Living Related Renal Allografts Allogenic Bone Marrow-derived Stem Cells 2) Better graft function but not statistically significant 1) Single acute rejection; 2) Appearance of CMV disease; 3) Serum creatine not significant level; 4) No GVHD5) rise of donor-specifi cytotoxic allo-antibodies
Trivedi et al46, 2007 Chronic kidney disease Kidney 357 . 36 Induce tolerance against MHC barriers Allogenic Bone marrow (BM)-derived and peripheral blood stem cell (PBSC) 1) Significantly better allograft function with low serum creatinine value 1) Acute rejection episode; 2) Acute vascular plus tubulointerstitial rejection; 3) Systemic infections; 4) Patients died
Vanikar et al47, 2014 end-stage renal disease Kidney 95 . 7 Safety, efficacy and benefits Mixed Adipose-derived mesenchymal stem cells (AD-MSC) + hematopoietic stem cells (HSC) 1) No side effects; 2) Survival rate is high; 3) safe and effectivestrategy for minimization of immunosuppression .
Khan et al48, 2010 Cirrhosis Liver 25 . . Safety and efficacy of human fetal liver-derived stem cell Allogenic Human fetal liver-derived stem cell 1) Decrease MELD score; 2) Improve clinical and biochemical parameters; 3) No episodes related to hepatic encephalopathy recurred No other clinical complications were observed after follow up
Sharma et al49, 2015 Liver cirrhosis Liver 55 18-70 3 Effect of peripheral CD+ cells Autologous Peripheral blood CD34+ cell 1) Procedure was safe; 2) Statistically significant - improve live function; 3) helps to delay liver transplantation .
Kumar et al50, 2009 Spinal cord injury Neuro 297 . . Safety and primary efficacy Autologous Bone marrow derived mononuclear cell 1) One-third patients show perceptible improvements; 2) No correlation between level of injury and improvements; 3) Number of CD34+ cells injected has direct correlation to outcomes In some - fever, Headache, Tingling sensation, Neuropathic sensory symptoms
Pal et al51, 2009 Spinal cord injury Neuro 30 . 3 Growth kinetics of BM MSC, safety and functional improvement Autologous Bone marrow-derived mesenchymal stem cell 1) Protocol is safe; 2) uncontrolled nature of the trial does notpermit demonstration of the effectiveness .
Venkataramana et al52, 2010 Parkinson’s Disease Neuro 7 . 36 Safety and feasibility of BM-MSCs Autologous Bone marrow-derived mesenchymal stem cell 1) Improvements in the UPDRS scale; 2) H&Y and S&E score also improved; 3) PD medication reduced .
Srivastava et al53, 2011 Cerebral palsy Neuro 30 5-25 12 To evaluate the feasibility, safety, therapeutic potential Autologous Bone marrow-derived mononuclear cells 1) Twopatient - fever; 2) Protocol - Safe; 3) mBI score - significantly improved; 4) MRC, Ashworth scale - significantly improved .
Bhanot et al54, 2011 Spinal cord injury Neuro 13 18-51 12 Safety and efficacy of Autologous Bone marrow-derived mesenchymal stem cells Only few patients shows improvement 1) 50% patients reported - a transient increase in spasticity; 2) In some - Fever, vomiting, general body ache, tingling/burning girdle sensation
Sharma et al55, 2012 Muscular dystrophy, spinal cord injury, cerebral palsy, and miscellaneous Neuro 71 . 15 Outcomes of autologous stem cell therapy Autologous Bone marrow derived mononuclear cell Shows improvements and also improves quality of life No adverse event
Venkataramana et al56, 2012 Parkinson’s Disease Neuro 12 37–69 12 Safety, feasibility, and efficacy of allogenic Allogenic Bone marrow-derived mesenchymal stem cells Subjective improvement observedreported clarity in speech, reduction in tremors, rigidity, and freezing attacks .
Aggarwal et al5,7, 2012 Posttraumatic Facial Nerve Paralysis Neuro 8 18-60 6 Safety profile and role Autologous Bone marrow-derived mononuclear cells 1) Significant improvement in ENoG amplitude; 2) statistically significant both for eyeclosure and for deviation of angle of mouth .
Sharma et al58, 2013 Autism Neuro 32 3-33 26 Safety, efficacy, and clinical effects Autologous Bone marrow-derived mononuclear cells 1) Statistically significant in CGI-I score and total ISAA score; 2) Not significant in FIM score and Wee-FIM scores; 3) CGI-II scale - global improvement 1) Seizures after therapy controlled using antiepileptic drugs; 2) In some - headache, nausea, vomiting backache, pain at the site of injection, aspiration; 3) Increase in hyperactivity at minimal and persistent level but not interfere with the global clinical improvement
Sharma et al59, 2013 Muscular dystrophy Neuro 150 2.11-8 Mean 12 Safety and Efficacy Autologous Bone marrow-derived mononuclear cells Neurological improvements in trunk muscle strength, limb strength No adverse events
Sharma et al60, 2015 Cerebral palsy Neuro 40 17 months-22 yr 6 to evaluate the efficacy Autologous Bone marrow-derived mononuclear cells 95% of patients showed improvements 1) The beneficial effect of MNC (stem cell instillation) onhip survival. Spinal headache, nausea, vomiting, pain at the site of injection, suffered diarrhoea
Rajput et al61, 2015 Muscular Dystrophy, Duchenne Neuro 11 . 36 Role in the cellular therapy Allogenic Human umbilical cord mesenchymal stem cells 1) Provide muscle stability; 2) Provide muscle strength in the distal and proximal lower limb; 3) Stability in muscle function of other body parts .
Sharma et al,62, 2015 Traumatic Brain Injury Neuro 14 12-65 6 To promote angiogenesis, axonal remodelling, neurogenesis and synaptogenesis Autologous Bone marrow-derived mononuclear cells 1) Improvements - speech, trunk, upper limb activity, muscle tone, voluntary control, ambulation, gait pattern, posture, balance, psychological status, cognition, memory, Adls; 2) improved functional outcome and enhanced quality of life Side effect noted - seizure
Chhabra et al63, 2016 Spinal cord injury, acute Neuro 21 . 12 The safety and feasibility Autologous Bone marrow-derived stem cells 1) No significant adverse effects; 2) No significant improvements; 3) procedure is safe and feasible; 4) No efficacy demonstrated .
Sharma et al64, 2018 Intellectual disability Neuro 58 4-45 . Safety, efficacy and clinical effects of autologous bone marrow mononuclear cell Autologous Bone marrow-derived mononuclear cells 1) Symptomatic improvements in the intervention the group showed after transplantation compared with rehabilitation 1) No adverse events were recorded; 2) In some - Fever, headache, vomiting
Sen et al65, 2012 Femoral Head Osteonecrosis Skeletomuscular 40 . . Evaluates the early results of BMNC instillation into the femur head Autologous Bone marrow-derived mononuclear cells 1) Statistically, significant differences in HHS and its domains (pain, function, deformity, and motion); 2) the beneficial effect of MNC on hip survival. .
Gupta et al66,2013 critical limb ischemia Skeletomuscular 20 . 24 Safety and efficacy Allogenic Bone marrow derived mesenchymal stem cell 1) Improvements - rest pain scores in both the arms SAE - death but not related to stem cells
Gupta et al67, 2016 osteoarthritis Skeletomuscular 60 . 12 Safety and efficacy Allogenic Bone marrow mesenchymal stromal cells 1) Trend towards improvement in subjective parameters; 2) Not statistically significant with placebo Knee pain and swelling
Gupta et al68, 2017 Critical limb ischemia (CLI) due to Buerger’s disease Skeletomuscular 36 38-42 24 Efficacy and safety of i.m. injection of allogenic BMMSC Allogenic Bone marrow-derived mesenchymal stem cells Benefit in both the primary endpoints (rest pain relief and ulcer healing) and most secondary endpoints (improvement in total walking distance, ankle brachial pressure index, and quality of life). 1) Two deaths were reported; 2) administered allogeneic cells did not adversely alter the immunological and lymphocytic profile
Mulekar69, 2003 Vitiligo Skin 122 12-70 12 To evaluate the usefulness of epidermal cell transplantation Autologous Melanocyte-keratinocyte 1) Excellent repigmentation; 2) Recurrence also observed .
Tegta et al70, 2006 Vitiligo Skin 20 . 3 Efficacy of Autologous melanocyte Autologous Melanocyte 210-250 cells/mm2 required for satisfactory repigmentation .
Dash et al71, 2009 Nonhealing Ulcers Skin 24 . 3 Assess the efficacy and feasibility Autologous Bone marrow-derived mesenchymal stem cells and mononuclear cells Significant improvement in pain-free walking distance and reduction in ulcer size .
Mohanty et al72, 2011 Vitiligo Skin 14 . . To evaluate the efficacy of a novel surgical method Autologous Melanocyte Greatly achieved repigmentation .
Sahni et al73, 2011 Vitiligo Skin 25 . . Compare results of autologous melanocyte trnasplanation with saline and serum Autologous Melanocyte 1) Own serum shows better results than saline; 2) Statistically significant DLQI score 1) Mild adverse events; 2) Halo phenomenon and infection at site of injection;3) Hyperpigmentation; 4) scarring at the donor site
Budania et al74, 2012 Vitiligo Skin 41 . 4 Comparison of techniques Autologous Melanocyte 1) Excellent re-pigmentation observed; 2) NCES better than SBEG .
Singh et al75, 2013 Vitiligo Skin 30 . 4 Compare NCES and NCORSHFS Autologous Melanocyte 1) Excellent repigmentation; 2) reduction in DLQI score; 3) Both Safe and effective; 4) NCES is superior to NCORSHFS None any adverse events reported
Vinay et al76, 2015 Vitiligo Skin 30 . 6 Clinical characteristics and treatment variables Autologous Melanocytes and hair follicle stem cells 1) Achieving optimum repigmentation; 2) a strong correlation between repigmentation at 24 week and number of melanocytes and HFSC transplanted; 3) absence of dermal inflammation .
Donaparthi & Chopra,77, 2016 Vitiligo Skin 11 . 6 Comparative efficacy Autologous Melanocyte epidermal 1) >90% repigmentation; 2) safe and effective method; 3) Smaller patches repigmented better than larger ones .
Kumar et al78, 2018 Vitiligo Skin 25 . 6 Clinical Efficacy, Viability and cell compositions of suspension Autologous Melanocyte-keratinocyte 1) More than 50% repigmentation; 2) More than 80% cell viability Recipient site infection
Thakur et al79, 2018 Vitiligo Skin 40 . 6 Efficacy of transplantation of NCES and NDCS vs NCES Autologous Melanocyte-keratinocyte 1) Combination of NCES and NDCS resulted in excellent response than NCES alone 1) Mild hyperpigmentation or hypopigmentation; 2) Post surgery perilesional halo developed
Sahoo et al80, 2019 localized facial volume loss Skin 10 15-24 6 Safety and efficacy Autologous Dermal mesenchymal stem cells 1) Improvement in dermal atrophy and lipoatrophy 1) Erythema, edema and mild to moderate pain at the site of injection
Gupta et al81, 2019 Vitiligo Skin 32 13-31 6 Compare the two techniques Autologous Melanocyte-keratinocyte 1) 49% repigmentation achieved; 2) No statistically significant between two techniques Reported 1) Hyperpigmentation; 2) Scarring; 3) achromatic fissures; 4) reactivation of disease
Mrigpuri et al82, 2019 Vitiligo Skin 30 . 4 Efficacy of NCES Autologous Melanocyte-keratinocyte 1) Good repigmentation .
Gunaabalaji et al83, 2020 Vitiligo Skin 20 . . Comparison of efficacy Autologous Melanocyte hair follicle cell suspension and noncultured epidermal cell and 1) ECS was better than HFCS in repigmentation of leukotrichia and vitiligo, although the difference was not statistically significant .

Outcome measure

The safety of the studies was measured based on the treatment protocol reported for stem cell therapy mentioned in these selected studies. This included obtaining stem cells from donors or patients, purification of stem cells (cultured or non-cultured), and injecting to the patients at the targeted site. The efficacy measured in the form of the outcome of the studies included clinical, biochemical, and behavioural parameters or the overall outcome of the study. Adverse events were recorded as: (i) no adverse events, (ii) mild or treatable adverse events, and (iii) serious adverse events, including death or malignancy.

Results

Overall, autologous stem cells (75%) were used dominantly for stem cell therapy as compared with allogenic stem cells (18.33%) followed by mixed type (6.67%). The bone marrow-derived stem cells (51%) were used prominently, followed by melanocytes (19%), adipose (7%), haematopoietic (12%), limbal (6%), dermal (2%), fetal liver (2%) and umbilical cord (1%) derived stem cells (Fig. 2).

Types of stem cells. MSCs, mesenchymal stem cells; SCs, stem cells.
Fig. 2.
Types of stem cells. MSCs, mesenchymal stem cells; SCs, stem cells.

Vitiligo (22%) emerged as the disease with a predominant use of stem cell therapeutics, followed by type 1 diabetes mellitus (8%), stroke (8%), spinal cord injury (8%), cerebral palsy (5%), muscular dystrophy (5%), type 2 diabetes mellitus (3%), limbal stem cell deficiency (3%), acute myocardial infarction (3%), cellular cardiomyoplasty (3%), kidney disease (3%), renal allograft (3%), cirrhosis (3%), Parkinson’s disease (3%), critical limb ischemia (3%), cystic maxillofacial bony defects (2%), autism (2%), ocular burns (2%), intellectual disability (2%), traumatic brain injury (2%), posttraumatic facial nerve paralysis (2%), femoral head osteonecrosis (2%), osteoarthritis (2%), facial volume loss (2%) and non-healing ulcers (2%). Figure 3 describes the use of stem cells for each disease category.

Types of diseases treated using stem cells during clinical trials.
Fig. 3.
Types of diseases treated using stem cells during clinical trials.

Lack of enough randomized clinical trials

There were lack of randomized clinical trials in the selected studies. Many studies were conducted without randomisation, had low sample sizes, and control groups were mostly absent (Table)23-83.

Status of selected clinical studies

Out of 61 selected studies, 37 studies reported clinical trials that were conducted in government research hospitals, and 24 clinical trials were conducted in non-government ones, based on the authors and their affiliated institutes mentioned in the research papers. However, only 16 studies mentioned the clinical trial registration number from the Clinical Trials Registry of India (CTRI number) or from clinicaltrials.gov. (National Clinical Trial (NCT) number). Of 61 selected studies, 56 mentioned approval or clearance from the Institutional Review Board, the Institutional Ethics Committee, or the Institutional Ethics Committee for Stem Cell Research (ICSCR).

Uses of stem cells for non-malignant diseases in terms of safety and efficacy

Stem cell therapy can be safe as a treatment protocol mentioned in the studies selected for this systematic review. The treatment protocol includes stem cell extraction from the patient or donor to reinjection of the stem cell aspirate at the specific site in the patient. During this procedure, selected studies did not mention any life-threatening adverse effects of this treatment protocol. However, few exceptions, such as infection or pain at the injection site or aspiration site, were reported32,43,49,79. The efficacy level of stem cell therapy varied according to disease type.

Skin diseases

Stem cell therapy for skin diseases like vitiligo, non-healing ulcers, and localized facial volume loss, etc., showed good safety and efficacy69-75. Though improvement in dermal atrophy and lipoatrophy was observed for localised facial volume loss, adverse effects like erythema, oedema, and pain at the injection site were also observed81. Non-healing ulcers treated using stem cells reported significant pain-free walking and reduced ulcer size71. In vitiligo, repigmentation was good, and percentages of repigmentation depended on the applied technique and cell concentration. Mild adverse events were also noted in a few studies, such as hyperpigmentation, halo phenomenon, infection at the site of injection, scarring at the donor site, achromatic fissures, and reactivation of vitiligo73,80-82.

Diabetes

Among diabetic trials, type 1 as well as type 2 diabetes mellitus, the use of stem cells showed increased c-peptide level, reduced HbA1c (haemoglobin A1c or glycated haemoglobin) level, and reduced insulin requirement, but GAD (glutamic acid decarboxylase) antibodies showed mixed results24-30. Bone marrow-derived stem cell transplantation type 2 diabetes mellitus patients did not show major complications. However, minor complications like nausea, vomiting, and hematoma were reported24. The type 1 diabetes showed significant outcomes in terms of reduction in insulin dose and HbA1c levels, and increased c-peptide levels24-27.

Dental diseases

In the dental field, the solitary trial outcome showed that the cystic maxillofacial defects were treated using autologous bone marrow-derived stem cells. After six months of followup, bone defect volume was reduced, tooth mobility was not observed, and faster wound healing was achieved23.

Eye diseases

Studies on eye diseases showed that limbal stem cell deficiency could be treated with limbal stem cells, but after a followup period, it showed increased epithelialized, avascular, stable corneal surface and visual acuity31-34. Live limbal stem cells showed better results in allogeneic transplantation than cadaveric limbal stem cells33.

Cardiovascular diseases

Stem cell therapy was used for stroke, myocardial infarction, cardiomyoplasty, cardiomyopathy, and heart failure35-43. For stroke, stem cell treatment showed improvement based on the Rankin scale and Barthel Index, which was statistically significant38. No significant outcomes were compared with the placebo; procedure-level safety was found, but serious adverse events were also noted37. The adverse events included ventricular tachycardia, pericardial effusion, chest pain dyspnoea, thrombosis, haematoma at the catheterization site, pain at the aspiration site, ventricular arrhythmia, and elevated serum creatinine level39-41.

Kidney-related diseases

Stem cell therapy has been tried for kidney-related diseases too in India, and it includes chronic kidney disease renal transplants, and end-stage renal disease44-47. This therapy helped renal transplantation to minimise the chances of graft rejection through allogenic stem cell therapy, and it was also used for minimizing immunosuppression47. The side effects include acute rejection, CMV disease appearance, and donor-specific cytotoxic alloantibodies45.

Liver disorders

The use of stem cell therapy for the treatment of liver cirrhosis has also been reported. Reports suggest its beneficial effect in improving liver function, improved clinical and biochemical parameters, and provided support to delay liver transplantation48,49.

Neurological diseases

Stem cell therapy has been used for neurological diseases such as facial nerve paralysis, spinal cord injury, autism, cerebral palsy, traumatic brain injury, intellectual disability, Parkinson’s disease, muscular dystrophy, and the outcomes showed mixed results50-64.

For Autism, stem cell therapy showed a significant difference between CGI (clinical global impression) and ISAA (Indian Scale for Assessment of Autism) scores, but not for FIM (Functional Independence Measure) and Wee-FIM scores58. Significant improvement in the mBI (modified Barthel Index) score, MRC (Muscle Power Scale), and Ashworth scale was found for cerebral palsy49,53. Symptomatic improvement was found for intellectual disability64. Neurological improvements in limb strength and stability in muscle function of the body parts were shown in muscular dystrophy after stem cell treatment55,58,61.

The use of stem cells for Parkinson’s disease showed improvement in the UPDRS (Unified Parkinson’s Disease Rating Scale) scale, H&Y (Hoehn and Yahr), and S&E (Schwab and England) scores that helped in the reduction its medication, tremors, rigidity, and freezing attacks, improved clarity in speech and subjective improvement52,56. In spinal cord injury, stem cell therapy protocol was safe, but at the efficacy level, only a few patients showed improvement; there was no correlation between injury and improvements50,51,54,63. In traumatic brain injury, stem cell therapy helped in the improvement of speech, trunk, upper limb activity, muscle tone, voluntary control, posture balance, and psychological status62. No serious adverse were noted for neurological disorders, but seizures, headache, fever, nausea, vomiting, backache, pain at the site of injection, diarrhoea, spasticity, and tingling sensation were reported as minor adverse events50,54,58,60,64.

Musculoskeletal disorders

In critical limb ischemia, stem cell therapy helped relieve pain and heal ulcers65-68. Serious adverse events were reported, resulting in two deaths, during the use of allogeneic stem cell therapy68. SCT also shows statistically significant results in HHS (Harris Hip Scale/Score) in hip survival, and subjective improvements were observed in osteonecrosis65.

Discussion

The findings of this study indicated that India is taking great interest in the benefits of melanocytes (extracted from hair follicle cell suspension) for treating vitiligo. Injection of hair follicle cell suspension containing melanocytes and keratinocytes was found to be useful in managing vitiligo76,77,79. Although there was a small population size in some studies, there was a trend towards an improvement in symptoms and disease outcomes in individuals who had received BM-MSC compared with controls56,57,66. Two deaths were also reported as serious adverse events when using allogeneic stem cell therapy68. On the other hand, statistically significant results were also shown that helped in hip survival, with subjective improvements in osteonecrosis65.

The findings from this systematic review address important gaps in stem cell therapeutics for non-malignant diseases in India. Study indicates that stem cell therapy could be safe for treating non-malignant, non-haematological diseases, but the smaller number of participants in these clinical trials is a cause of concern. This study highlights important factors that are expected to shape the future of stem cell research and therapy in India. It may include standardization, regulations, basic research and clinical trials support, trained human resources, and infrastructure84. Maintaining the gold standard for stem cell therapy requires randomized clinical trials with a large sample size to study success, failures, adverse effects, etc8,85,86.

Future trials would need to incorporate more robust outcome measures that are patient-centered, and RCTs should be done instead of cohort studies and clinical trials with a small number35,57,59,62. Studies on assessing potential barriers and enablers to both patient participation and physician involvement in early-phase clinical trials are limited. This is an important knowledge gap that needs to be addressed for safety outcomes in stem cell therapy and research. This study also revealed that government hospitals published more studies than non-government hospitals.

India is aware of the potential of stem cell science, and the key question is, to what extent is India sensitive to the emerging challenges or barriers to stem cell therapeutic commercialization, its clinical implications, and its position in the global scenario? The other question arises: What should be done about desperate patients paying out of pocket for unproven treatments? The factors that affect such clinical practice and research in the public arena need to be identified. There is a need to synthesize more knowledge in stem cell research and therapeutics.

The study limitations include inability to use meta-analysis because of the qualitative outcome of all studies, the smaller number of clinical trials, the low sample size in some disease categories, the significant diversity of diseases, or study heterogeneity.

Overall, we need more clinical studies and the stakeholders’ perspectives on stem cell therapy to shift from experimental interventions into routine clinical practice. Despite the potential of stem cell and regenerative medicine research for safety and efficacious outcomes, there is potential for stem cell treatment in non-haematological diseases. However, well-controlled, randomized, large-scale trials are required to establish safety and efficacy. Clinical trials need to be reviewed by IC-SCR, and prospective interventional trials need to be registered with CTRI. Our findings are a call to action to stakeholders (clinicians, industries, policymakers, researchers, etc.) to identify approaches for stem cell therapy that are best suited for treating non-malignant diseases and non-haematological and accordingly can plan to invest resources for further research and development for a particular disease.

Acknowledgments

The authors acknowledge the Director, CSIR-NIScPR, New Delhi, India, for providing the support and guidance needed to complete the manuscript.

Financial support & sponsorship

None.

Conflicts of Interest

None.

Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation

The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.

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