Table 2.

Recent advancements in clinical trials utilizing MSCs for the treatment of diverse diseases

Diseases	Cell source	Route	Dose	Frequency	Patients (experiment group)	Clinical Trials number	Study phase	Outcomes	Ref
GVHD	BM	i.v.	2 × 106 cells/kg	Twice a week, in total four weeks	54	NCT02336230	III	Remestemcel-L infusions significantly improved overall response in pediatric patients with SR-aGVHD and were well tolerated with no identified safety concerns. The improved response on day 28 was strongly associated with significantly improved survival through day 180.	68
GVHD	BM	i.v.	2 × 106 cells/kg	One, two, or four times a week	15	NCT02359929	I	No dose-limiting toxicities. Three patients had responses seen at any timepoint. No difference was seen among dose levels in peripheral blood lymphocyte subsets.	470
GVHD	BM	i.v.	1 × 106 cells/kg	Once a week, 4 weeks	101	NCT02241018	III	The most common adverse events were infections and hematological toxicity. The OR on day 28 and 56 was higher in the MSC group. The median failure-free survival was also longer in the BM-MSCs group. The cumulative incidence of cGVHD was lower than the control group.	471
GVHD	BM	i.v.	2 × 106 cells/kg	At least 6 times	11	NCT01522716	II	Displayed a distinct immune phenotype characterized by higher levels of naive T cells and B cells, and a significantly higher fraction of CD31+ naive CD4 + T cells.	472
GVHD	BM	i.v.	1.5–3 × 106 cells/kg	Once	23	NCT01045382	NA	One-year OS remain no change. No difference was observed in the incidences of chronic GVHD, infection or relapse, overall or progression-free survival	473
GVHD	BM	i.v.	1.5 × 107 cells/kg	Once	5	000024291	I	All patients demonstrated successful recovery of neutrophil, reticulocyte, and platelet. At 1 year, all MSC‐CBT patients survived without relapse.	474
GVHD	UC	i.v.	1 × 106 cells/kg	Once	25	ChiCTR-INR-16008399	II	Promoted platelet engraftment and decreased severe acute GVHD without increasing relapse rate.	475
GVHD	UC	i.v.	1 × 106 cells/kg	Once every 2 weeks, 4 doses in total	78	ChiCTR-IIR-16007806	NA	The MSC group had better GVHD-free and relapse-free survival rates than the control group.	476
GVHD	UC	i.v.	1–2 × 106 cells/kg	Twice a week, 2–4 weeks in total	7	UMIN000032819	I	Three subjects showed complete response. NK cell counts significantly increased, whereas IL-12, IL-17, and IL-33 levels decreased.	477
GVHD	BM	i.v.	0.9–1.3 × 106 cells/kg	Once	43	NCT01941394	NA	It exerted a positive effect on the restoration of T-cell subpopulations and immune system recovery.	478
GVHD	Extraembryonic fetal tissues	i.v.	2–10 × 106 cells/kg	On day 0 and 7	10	NCT03158896	I	The ORR of clinical response on day 28 was 70%. Day 100 and 180 post infusion survival was 90% and 60%. Serum biomarker REG3α decrease correlated with clinical response.	479
GVHD	Induced pluripotent stem cells	i.v.	1 × 106 or 2 × 106 cells/kg	On day 0 and 7	16	NCT02923375	I	No serious adverse events. OR, CR and OS rates by day 100 were 86.7, 53.3 and 86.7%.	480
GVHD	BM	i.v.	1.0 × 106 cells/kg	Once every 2 weeks, 4 doses in total	10	KCT0001894	I/II	It revealed a reduction in inflammatory markers. All patients showed amelioration of clinical symptoms and enhancement of their quality of life.	481
GVHD	UC	i.v.	1.0 × 106 cells/kg	Twice a week, 4–8 weeks	40	ChiCTR2000035740	II	The 2-year cumulative incidence of moderate to severe cGVHD was marginally lower in MSC group than in the control.	482
GVHD	UC	i.v.	1.0 × 106 cells/kg	A median of four times	86	NCT01754454	NA	24 patients achieved complete remission, while 21 exhibited partial remission. The survival rate was approximately 11.6%.	483
SLE	BM	i.v.	2–3 × 106 cells/kg	Once	7	NCT03174587	I	3 adverse events were reported, one diarrhea, one toothache, and one arthralgia.	484
SLE	BM or UC	i.v.	1 × 106 cells/kg	Once or twice	69	NCT00698191 andNCT01741857	NA	40 participants achieved low disease activity and 16 participants reached clinical remission.	485
SLE	UC	i.v.	1 × 106 cells/kg	Once	6	NCT03171194	I	5 participants achieved the clinical endpoint. The autoantibody levels were decreased. Tregs of 2 participants increased, but other T cells had no significant changes.	486
SLE	Adipose	i.v.	2 × 106 cells/kg	Once	9	NA	I	Allogenic AD-MSC transplantation was associated with favorable safety and efficient to reduce urine protein excretion and disease activity. Meanwhile, the greatest improvement happened at a month based on the proteinuria.	487
RA	BM	i.v.	1 × 106 cells/kg	Once	13	NA	NA	Increased FOXP3, IL-10 and TGF-β1 in PBMCs.	488
RA	Adipose	i.v.	2 × 108 cells	Once	15	NCT03691909	I/IIa	No adverse events. ACR66/68 scores significant improved, levels of TNF-α, IL-6 and ESR remained unchanged.	489
RA	UC	Intravenous drip	2 × 107 cells	Once	64	NCT01547091	NA	The ESR, CPR, RF and anti-CCP after treatment were detected to be lower than that of pretreatment.	490
RA	UC	Intravenous drip	1 × 106 cells/kg	Once	63	ChiCTR-INR-17012462	I/II	No unexpected safety issues, the efficacy and ACR20 response rates were higher.	491
UC	BM	i.v.	1.5 × 106/kg	Once	4	NCT04543994	I/II	At 3 months, all patients were satisfied with MSC treatment based on the inflammatory bowel disease patient-reported treatment impact.	492
UC	UC	i.v.	1 × 108 cells	Biweekly, 3 times in total	6	NCT03299413	I	No significant short-term or intermediate-term adverse events were detected post-UCMSC administration. Long-term follow-up at 12 and 24 months showed sustained safety and no adverse events.	493
CD	BM	Intralesional	3 × 107 cells	Once	16	N.A.	N.A.	Open-label injection of BM-derived MSCs was safe and was effective in half of patients in fistulizing perianal CD and induced significant MRI changes associated with favorable clinical outcome.	494
CD	BM	Intralesional	3 × 107 cells	Once	10	N.A.	I/II	4 patients were hospitalized due to occlusion. At 12 weeks, 5 patients presented a complete or partial resolution of the stricture. There were no adverse or serious adverse events related to MSC therapy. At 6 months, 31% of the treatment group and 20% of the control had complete clinical and radiographic healing.	495
CD	BM	i.v.	7.5 ×107 cells	Once or twice	16	NCT04519684	I/II	No adverse events. PCDAI, Wexner incontinence score, and van assche score significantly decreased in treatment patients.	496
CD	BM	Intralesional	1–9 × 107 cells	Once	21	NCT01144962	N.A.	Two malignancies were observed. No serious adverse events. 63%, 100%, and 43% of the fistulas were closed in 3 cohorts, respectively. MRI showed significantly smaller fistula tracts.	141
CD	BM	Intralesional	7.5 × 107 cells	Once	10	CTRI/2020/01/022743	I/II	At week 52, two patients were in remission and seven maintained responses. At 104 weeks, two patients maintained response and one was in remission.	497
CD	BM	Intralesional	7.5 × 107 cells	Once	7	N.A.	I	No adverse events. At 6 months, 83% had complete clinical and radiographic healing.	498
CD	BM	Intralesional	7.5 × 107 cells	Once	15	N.A.	Ib/IIa	50% of the treatment group had complete clinical and radiographic healing; 91.7% of the treatment group had improvement	499
CD	Adipose	Intralesional	N.A.	Once	20	N.A.	I	4 patients experienced 7 serious adverse events and 12 patients experienced 22 adverse events.	500
CD	Adipose	Intralesional	1.2 × 108 cells	Once	25	NCT01541579	III	7 serious adverse events occurred. Clinical remission was reported in 56% patients.	501
CD	Adipose	Intralesional (MSCs-Matrix)	N.A.	Once	5	N.A.	I	All patients had a reduction in the size of fistula tract, and 3 of 5 had cessation of drainage, but none achieved complete healing.	502
CD	UC	Intralesional	1.2 × 108 cells	Once	10	NCT04939337	N.A.	No adverse events occurred. The fistulas decreased, Significant improvement in Perianal CD Activity Index, Pelvic MRI-Based Score, and quality of life score on 24 W.	503
CD	Adipose	Intralesional	1.09–4.78 × 106 cells/kg	Once	10	N.A.	N.A.	7 patients had clinical responses. A decreased PDAI score and an increased quality of life score.	504
CD	Adipose	Intralesional	2 × 107 cells	Once	15	N.A.	I	No serious adverse events. 3 patients had complete clinical healing, 8 patients had partial healing, and 4 patients showed no clinical improvement.	505
CD	Adipose	Intralesional	N.A.	One, two or three times	21	NCT03803917	I	57% of patients had complete fistula healing.	506
CD	UC	i.v.	1 × 106 cells/kg	8 doses in 5 months	8	N.A.	I	The clinical symptoms and signs of patients with CD were substantially relieved (CDAI, CRP, ESR). The genus Cetobacterium was significantly enriched	507
CD	BM	Intralesional	1.5–3 × 108 cells	Once	6	NCT04548583	Ib/IIa	Seven adverse events occurred. SES-CD and CDAI score decreased.	508
ARDS	BM	i.v.	1 × 107 cells/kg	Once	60	NCT02097641	II	No patient experienced any adverse events. 28-day mortality did not differ between the groups, The MSC group had higher APACHE III scores, minute ventilation and PEEP.	509
COVID-19	BM-MSC-EV	i.v.	15 mL	Once	25	NCT04493242	N.A.	The treated patients had a restored oxygenation, reduced cytokine storm and modulated immunity.	510
COVID-19 ARDS	BM	i.v.	1 × 106 cells/kg	2 or 3 doses	23	432/2020BO	I	The MSCs infusion was safe. The group had a significantly higher Horovitz score on discharge.	511
COVID-19 ARDS	BM	i.v.	1 × 106 cells/kg	Once	20	NCT04615429	N.A.	It was safe and may be beneficial, in low mortality, accelerating clinical recovery and hospital discharge	512
COVID-19 ARDS	UC	i.v.	1 × 108 cells	Once or twice	19	IRCT20200217046526N2	II	It reduced the levels of inflammatory markers in patients, with no serious adverse events.	513
COVID-19 ARDS	Placenta	i.v.	1 × 106 cells/kg	Once	10	IRCT20200621047859N4	I	No adverse events. Length of hospitalization, serum oxygen saturation, and other clinical and laboratory parameters were same.	514
COVID-19 ARDS	UC	i.v.	1 × 106 cells/kg	3 times every other day	10	IRCT20160809029275N1	I	No serious adverse effects. It declined cytokine storm and recover respiratory functions	515
COVID-19 ARDS	BM	i.v.	9 × 108 cells	Once	20	NCT03807804	II	No significant difference in the number of VFDs but may result in improved survival	516
COVID-19 ARDS	UC	i.v.	1 × 106 cells/kg	3 times at 48 h intervals	22	NCT04333368	N.A.	No patient required oxygen support. Quality of life improved throughout the follow-up period, and the six-minute walking distance remained slightly impaired. No adverse effects	517
COVID-19 ARDS	Placenta	i.v.	1 × 106 cells/kg	Once or twice	10	IRCT2017010531786N1	N.A.	It improved oxygenation and pulmonary infiltrates, decreased inflammatory cytokine level.	518
COVID-19 ARDS	BM	i.v.	1 × 107 cells/kg	Once	17	NCT02097641	IIa	It significantly reduced airspace total protein, Ang-2, IL-6.	519
COVID-19 ARDS	BM	i.v.	2 × 106 cells/kg	Twice	113	NCT04371393	N.A.	No adverse events. No differences in days alive off ventilation	520
COVID-19 ARDS	UC	i.v.	1 × 106 cells/kg	Once	20	NCT04457609	N.A.	It increased the survival rate. The length of stay in the intensive care unit and ventilator usage were not significant, and no adverse events.	521
COVID-19 ARDS	UC	i.v.	2 × 108 cells	3 times every other day	11	N.A.	N.A.	It improved respiratory distress and reduced inflammatory biomarkers (IL-6, IFN-γ, TNF-α).	522
COVID-19 ARDS	UC	i.v.	0.8–1.2 × 108 cells	Twice at days 0 and 3	12	N.A.	I/IIa	No serious adverse events. Inflammatory cytokines were decreased. patient survival and time to recovery were improved.	523
COVID-19 ARDS	UC	i.v.	1–10 × 106 cells/kg	Once	9	1066023736	I	No adverse events. It decreased inflammatory biomarkers and increased immune cell markers	524
COVID-19	BM	i.v.	1 × 106 cells/kg	Once	7	ChiCTR2000029990	N.A.	The pulmonary function and symptoms of all patients were significantly improved. 2 common and 1 severe patient were recovered. Peripheral lymphocytes level increased. CRP decreased. The level of TNF-α decreased, while the level of IL-10 increased.	525
COVID-19	BM	i.v.	1.5–3 × 106 cells/kg	Every 3 days, 3 doses in total	8	NCT04445454	I/II	The BMSCs group shows very promising efficacy in severe COVID-19, with a higher survival compared to control patients.	526
COVID-19	BM-MSC-EV	i.v.	10 mL or 15 mL	Once or twice	102	NCT04493242	II	No treatment-related adverse events. Mortality (60-day) in the intention-to-treat population was reduced. Ventilation-free days improved for all patients.	527
COVID-19	Placenta	i.v.	1.5–2 × 109 EVs/kg	Twice in two days	21	IRCT20130812014333N164	N.A.	hPMSC-sEVs reduced the mortality rate in the intervention group compared to the controls.	528
OI	BM	i.v.	4 × 106 cells/kg	Once every 5–6 months, 5 times in total	2	NCT02172885	I	Elicited a pro-osteogenic paracrine response in patients and improved the qualities of life by bettering bone parameters.	529
OI	Fetal liver	i.v.	3 × 106 cells/kg	Once every month for 4 months	18	NCT03706482	I/II	Not yet public	530
OA	UC	Intra-articular	2 × 107 cells	Once	10	NCT06078059	N.A.	Not yet public	531
OA	UC	Intra-articular	2 × 107 cells	On 0 and 6th month	9	NCT02580695	I/II	Pain visual analog scale and WOMAC score decreased significantly	532
OA	BM	Intra-articular	2.5 × 107 cells	Once	65	CTRI/2018/09/015785	III	WOMAC and visual analog scale scores were significantly improved, the cartilage volume remained unchanged, and there was no deterioration observed in the deep cartilage of the medial femorotibial compartment of the knee	533
OA	Adipose	Intra-articular	1 × 108 cells	Once	18	IRCT20080728001031N23	II	Decreased hyaluronic acid and cartilage oligomeric matrix protein levels in blood serum in patients, and affected multiple biomarkers in blood samples.	534
OA	UC	Intra-articular	1 × 107 units	Every week for 3 weeks	29	NCT03800810	II	hUC-MSCs decreased pain in severe KOA and improved the knee functions in combination with HA.	535
OA	BM	Intra-articular	1–50 × 106 cells	Once	12	NCT02351011	I/II	There were significant improvements in KOOS pain, symptoms, and quality of life and WOMAC stiffness, with the most obvious improvements in the 50 million dose cohort	536
OA	Adipose	Intra-articular	1 × 108 cells	Once	12	N.A.	IIb	Functional improvement and pain relief without causing apparent adverse events at 6 months’ follow-up.	537
OA	Adipose	Intra-articular	1 × 108 cells	Once	3	IRCT20080728001031N23	I	VAS, WOMAC and KOOS were significantly improved, with no serious adverse events	538
SCI	BM and UC	Intrathecal	1 × 106 cells/kg	Biweekly, 3 times in total	20	NCT04288934	I/II	MSCs enhanced recovery from spinal cord injury and facilitate motor function improvements	539
Stroke	BM	Intranasal	4.5–5 × 107 cells	Once	10	NCT03356821	N.A.	Safe and feasible.	540
Stroke	Adipose	i.v.	1 × 106 cells/kg	Once	15	NCT04280003	IIb	Not yet public	541
Stroke	Adipose	i.v.	1 × 106 cells/kg	Once	4	NCT01678534	IIa	Safe and no injection-related tumor developments were reported.	542
Stroke	BM	Intrathecal	1 × 106 cells/kg	once every week for a month	59	ChiCTR-INR-16008908	II	Not yet public	543
Stroke	BM	i.v.	2 × 106 cells/kg	Once	9	NCT01461720	II	The absolute change of median infarct volume in patients treated with MSCs was improved, and the average cumulative number of GEL was decreased.	544
MI	UC	Intracoronary	2 × 107 cells	Once	20	IRCT20201116049408N1	N.A.	Not yet public	545
MI	UC	Intracoronary	1 × 107 cells	Once	130	NCT05043610	III	Not yet public	546
MS	UC	i.v. and intrathecal	3 × 108 or 1.5 × 107 cells	1 or 2 doses	35	NCT03326505	I/II	Both groups showed better motor function, radiology, cognitive, sleep, immunological outcomes. Two doses can be more beneficial.	547
AD	UC	Lateral ventricle	1 or 3 × 107 cells	Once every 3 months, 4 times in total	9	NCT02054208, NCT03172117	I	Total tau, phosphorylated tau, and Aβ in the CSF samples were reduced. Galectin-3, sICAM-1, progranulin and GDF-15 were increased one day after MSC transplantation, while decreased sharply within 4 weeks.	548
ALS	BM	Intrathecal	1 × 106 cells/kg	Once	24	NCT0291768	I/II	Identified 220 deregulated proteins in CSF of ALS patients treated with MSCs by Proteomics analysis.	549
ALS	BM	Intrathecal	1 × 106 cells/kg	2 or 5 doses	69	NCT04745299, KCT0005954	III	Not yet public	550
ALS	BM	Intrathecal and Intramuscular	1.25 × 108 cells and 4.8 × 107 cells	Once	36	NCT02017912	II	Rate of disease progression was improved at early time points. CSF neurotrophic factors increased and CSF inflammatory biomarkers decreased.	551
Diabetes	BM	i.v.	1 × 106 cells/kg	Twice, on week 0 and 3	11	NCT04078308	I/II	Early autologous MSC transplant in new T1D children with hypoglycemia is safe and promising.	412
Diabetes	UC	i.v.	2.5–20 × 107 cells	Once	14	NCT03406585	I/II	ProTrans MSCs are safe for new-onset T1D and may preserve beta cells.	552
Diabetes	UC	i.v.	1 × 106 cells/kg	3 times in 4-week intervals	37	NCT02302599	N.A.	Men with T2DM and high AUCC-pep are more likely to benefit from UC-MSC treatment.	553
Diabetes	UC	i.v.	1 × 106 cells/kg	Once a week for 3 weeks	24	ChiCTR2200057370	II	hUC-MSCs are safe for T2DM, causing mild side effects, and may modulate immunity and lymphocytes.	554
Diabetes	UC	i.v.	1 × 106 cells/kg	3 times at 4-week intervals	45	NCT02302599	II	The MSCs group reduced insulin percentage, HbA1c level and increased the glucose infusion rate compared with the placebo group.	415
Diabetes	UC	i.v.	1 × 106 cells/kg	Twice in 3 months	27	ChiCTR2100045434	N.A.	It is safe for new-onset T1D patients and may preserve islet β cells in the initial year following diagnosis better than standard care alone.	555
Diabetes	UC	i.v.	2 × 105 cells/kg	3 times on 0/7/28 day	14	ChiCTR2200055885	I	hUC-MSCs benefit DFU healing, with good tolerance, faster healing, and a higher 3-year amputation-free survival rate.	556
Prostate Cancer	BM	i.v.	1 × 106 or 2 × 106 cells/kg	Once	7	NCT01983709	I	Unmodified MSCs do not seem viable for delivering antitumor therapy to primary prostate cancer.	557

i.v. intravenous, GVHD graft-versus-host disease, SLE Systemic lupus erythematosus, RA Rheumatoid arthritis, UC ulcerative colitis, CD Crohn’s disease, ARDS Acute respiratory distress syndrome, COVID-19 Coronavirus disease 2019, OI Osteogenesis imperfecta, OA Osteoarthritis, SCI spinal cord injury, MI myocardial infarction, MS multiple sclerosis, AD Alzheimer’s disease, ALS amyotrophic lateral sclerosis, BM bone marrow, UC umbilical cord, BM-MSC-EV bone marrow mesenchymal stem cell-derived extracellular vesicles, N.A. not applicable, OR overall response, OS overall survival, CBT cognitive behavioral therapy, IL-17 overall survival, IL-33 interleukin-33, ORR overall response rate, REG3a regenerating islet-derived protein 3a, OR odds ratio, CR complete response, FOXP3 forkhead box P3, IL-10 interleukin-10, TGF-β1 transforming growth factor-beta 1, PBMCs peripheral blood mononuclear cells, TNF-α tumor necrosis factor-alpha, ESR erythrocyte sedimentation rate, CRP C-reactive protein, RF rheumatoid factor, anti-CCP anti-cyclic citrullinated peptide, HAQ health assessment questionnaire, DAS28 disease activity score 28, MRI magnetic resonance imaging, CD Crohn’s disease, PDAI Pouchitis disease activity index, CDAI Crohn’s disease activity index, SES-CD simple endoscopic score for Crohn’s disease, APACHE III Acute Physiology and Chronic Health Evaluation III, PEEP positive end-expiratory pressure, VFDs ventilator-free days, PaO2/FiO2 partial pressure of arterial oxygen to fractional inspired oxygen, Ang-2 angiopoietin-2, IFN-γ interferon-gamma, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index, KOA knee osteoarthritis, HA hyaluronic acid, KOOS knee injury and osteoarthritis outcome score, VAS visual analog scale, Aβ42 amyloid-beta 42, CSF cerebrospinal fluid, CAM-1 cell adhesion molecule-1, GDF-15 growth differentiation factor-15, ALS amyotrophic lateral sclerosis, T1D type 1 diabetes, T2DM type 2 diabetes mellitus, AUCC area under the curve of continuous data, HbA1c hemoglobin A1c, DFU diabetic foot ulcer