Safety of intravascular administration of umbilical-cord-derived mesenchymal stromal cells: an updated systematic review and meta-analysis

Christine Hum; Jessica Poliwoda; Manoj Lalu; Duncan J Stewart; Shirley H J Mei; Keith R Walley; John Marshall; Asher A Mendelson; Dean A Fergusson; Shane English; Brent W Winston; John Granton; Claudia C dos Santos; Josee Champagne; Lauralyn McIntyre

doi:10.1093/stcltm/szag029

. 2026 Jun 5;15(6):szag029. doi: 10.1093/stcltm/szag029

Safety of intravascular administration of umbilical-cord-derived mesenchymal stromal cells: an updated systematic review and meta-analysis

Christine Hum ¹, Jessica Poliwoda ², Manoj Lalu ^3,^4,^5,⁶, Duncan J Stewart ^7,⁸, Shirley H J Mei ⁹, Keith R Walley ¹⁰, John Marshall ¹¹, Asher A Mendelson ¹², Dean A Fergusson ^13,¹⁴, Shane English ^15,^16,¹⁷, Brent W Winston ¹⁸, John Granton ¹⁹, Claudia C dos Santos ²⁰, Josee Champagne ²¹, Lauralyn McIntyre ^22,^23,^24,^✉

¹ Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

² Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada

³ Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

⁴ Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

⁵ Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada

⁶ Department of Anesthesiology and Pain Medicine, University of Ottawa, The Ottawa Hospital, Ottawa, ON, K1H 8L6, Canada

⁷ Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

⁸ Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada

⁹ Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

¹⁰ Department of Medicine, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, V6Z 1Y6, Canada

¹¹ Department of Surgery (Critical Care), St. Michael’s Hospital, University of Toronto, Toronto, ON, M5T 1P5, Canada

¹² Section of Critical Care Medicine, Department of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R3E 3P5, Canada

¹³ Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

¹⁴ Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada

¹⁵ Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

¹⁶ Department of Medicine (Critical Care), The Ottawa Hospital, Ottawa Hospital Research Institute, Centre for Transfusion and Critical Care Research, Ottawa, ON, K1H 8L6, Canada

¹⁷ Department of Medicine (Division of Critical Care), University of Ottawa, Ottawa, ON, K1H 8L6, Canada

¹⁸ Department of Critical Care, Medicine, and Biochemistry and Microbiology, University of Calgary, Calgary, AB, T2N 1N4, Canada

¹⁹ Department of Medicine (Critical Care), University of Toronto, Toronto, ON, M4N 3M5, Canada

²⁰ Keenan Research Centre for Biomedical Science and Interdepartmental Division of Critical Care, St. Michael’s Hospital, University of Toronto, Toronto, ON, M5B 1W8, Canada

²¹ Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

²² Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

²³ Department of Medicine (Critical Care), The Ottawa Hospital, Ottawa Hospital Research Institute, Centre for Transfusion and Critical Care Research, Ottawa, ON, K1H 8L6, Canada

²⁴ Department of Medicine (Division of Critical Care), University of Ottawa, Ottawa, ON, K1H 8L6, Canada

^✉

Corresponding author: Lauralyn McIntyre, Department of Medicine (Critical Care), The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada (lmcintyre@ohri.ca).

Roles

Christine Hum: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing

Jessica Poliwoda: Data curation, Writing - original draft, Writing - review & editing

Manoj Lalu: Conceptualization, Writing - original draft, Writing - review & editing

Duncan J Stewart: Conceptualization, Writing - original draft, Writing - review & editing

Shirley H J Mei: Conceptualization, Writing - original draft, Writing - review & editing

Keith R Walley: Writing - original draft, Writing - review & editing

John Marshall: Writing - original draft, Writing - review & editing

Asher A Mendelson: Writing - original draft, Writing - review & editing

Dean A Fergusson: Conceptualization, Writing - original draft, Writing - review & editing

Shane English: Writing - original draft, Writing - review & editing

Brent W Winston: Writing - original draft, Writing - review & editing

John Granton: Writing - original draft, Writing - review & editing

Claudia C dos Santos: Writing - original draft, Writing - review & editing

Josee Champagne: Project administration, Writing - original draft, Writing - review & editing

Lauralyn McIntyre: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Supervision, Writing - original draft, Writing - review & editing

PMCID: PMC13237491 PMID: 42246109

Abstract

Background

Mesenchymal stromal cells (MSCs) have the capacity to self-renew and exert immunomodulatory and paracrine effects. Our previously published systematic review of 55 randomized controlled trials (RCTs) of all MSC sources found an overall favorable safety profile for MSCs aside from more frequent fever in the MSC group.

Objective

Umbilical cord MSCs (UC-MSCs) possess potential biological and economic advantages over other MSC sources. Since several UC-MSC RCTs have been recently published in a heterogenous group of disorders, we performed a systematic review to specifically examine the safety profile of adult UC-MSC RCTs, while also providing quantitative syntheses (meta-analyses) of prespecified adverse events.

Methods

A systematic search was performed up to August 2025. RCTs were identified that compared intravascular delivery of UC-MSCs in adults to a control group. The primary outcome was safety categorized by the following prespecified adverse events with potential relevance to UC-MSCs: (1) fever and (2) non-fever acute infusional toxicity within 24 hours of study product administration, (3) infection, (4) death, (5) malignancy/ectopic tissue formation, (6) thrombotic/thromboembolic events, and (7) mycotic aneurysms. Prespecified adverse events were pooled and meta-analyzed.

Results

A total of 9160 studies were screened and 42 UC-MSC RCTs (n = 2280 patients) were included. UC-MSCs were associated with increased risk for fever (relative risk [RR] =2.34, 95% confidence interval [CI] =1.02-5.35). None of the other prespecified adverse events were associated with signals for harm. No included trials were stopped early due to safety concerns.

Conclusions

UC-MSC therapy appears safe for study in heterogeneous patient populations.

Keywords: mesenchymal stromal cell, umbilical cord, randomized controlled trial, systematic review, safety

Graphical Abstract

For image description, please refer to the figure legend and surrounding text.

Significance statement.

UC-MSCs are a potential therapy for treating complex life-threatening conditions. We conducted a systematic review to examine the safety of UC-MSCs in randomized controlled trials. We found that UC-MSCs were associated with increased risk of fever. There were no signals for harm related to other infusional toxicity events, infection, malignancy, thrombotic/thromboembolic events, death, or mycotic aneurysms, which increases the confidence that UC-MSCs appear safe. It is important for investigators to continue reporting on the occurrence of rare events such as thromboses and malignancies, the latter of which may require an extended follow-up duration for their detection.

Introduction

Mesenchymal stromal cells (MSCs) are plastic-adherent cells that have the capacity to self-renew and differentiate into various cell lineages.¹ They can be isolated from various tissues, including, but not limited to umbilical cord, bone marrow, and adipose tissue. These cells have been increasingly recognized for their therapeutic potential for numerous diseases. Scientific evidence suggests that the mechanism behind MSCs’ clinical benefit lies in their immunomodulatory and paracrine effects.² MSCs can inhibit or promote the function of leukocytes, exert antiproliferative effects, and promote angiogenesis.³^,⁴

Although MSCs have significant therapeutic potential, they also have potential risks. Examples include the development of fever,⁵ which could be directly related to the MSCs themselves, components in the infusion bag, or the manufacturing procedure, infection due to MSCs’ immunomodulatory effects,⁶ thromboses since MSCs can express tissue factor and other coagulation proteins,^7–9 and the development of malignancies due to the MSCs’ paracrine effects or through implantation in tissues.¹⁰^,¹¹ In 2019, our group published a systematic review of 55 adult randomized controlled trials (RCTs) that included MSCs derived from all sources along with prespecified adverse event categories to examine potential MSC-associated risks.¹² No adverse event signals other than the development of fever within 24 hours after administration of the study product were observed. However, some of the events are rare and require an extended follow-up period (eg, thromboses and malignancy, respectively) for their detection. As such, it is important to continue to evaluate them as additional published trials accumulate.

Umbilical cord-derived MSCs (UC-MSCs) represent an especially attractive MSC source for study. Their simpler isolation procedure and potentially lower costs to manufacture, greater self-renewal capacity, and lower immunogenicity are some reasons for the increased therapeutic interest in UC-MSCs as compared to other types of MSCs.^13–15 Three systematic reviews have evaluated the safety of UC-MSCs specific to the knee osteoarthritis and coronavirus disease-19 populations and concluded that UC-MSCs were safe.^16–18 These reviews provide quantitative syntheses for mortality as well as the incidence of all adverse events and/or serious adverse events (SAEs) in aggregate. Other than mortality, none of them included a priori adverse event categories or conducted meta-analyses on adverse events that are potentially relevant to UC-MSCs.¹⁶^,¹⁷ Our systematic review and meta-analyses materially advance the current understanding by summarizing the safety of UC-MSCs in heterogeneous patient populations, while also providing quantitative syntheses (meta-analyses) of prespecified adverse events that include rare adverse events and events that require a longer follow-up duration for their detection, such as thromboses and malignancies, respectively.

Methods

The methods of this updated systematic review and meta-analysis were adapted from our previously published reviews¹²^,¹⁹ with one main modification: in this current review, we only included studies that evaluated UC-MSCs. We also added an additional prespecified adverse event category for mycotic aneurysm (as this adverse event was observed in one patient in our phase I trial) and excluded studies published in abstract form only. Since this review is an update of a previously published review with only minor modifications, we did not register a separate protocol. Reporting of this review follows the PRISMA guidelines.

Search strategy and eligibility criteria

We conducted electronic searches of Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from inception up to August 22, 2025, using search strategies developed in conjunction with an information specialist (Supplementary Appendix I). ClinicalTrials.gov was also searched for recently completed trials with published results. All searches were performed without language restrictions, and if a non-English study met eligibility criteria, it was translated for data extraction.

We included RCTs that examined the intravascular (intravenously or intra-arterially) administration of UC-MSCs, compared to a control group that did not receive UC-MSCs, in adult populations. We excluded studies that used other types of MSCs, used non-intravascular routes of administration (eg, injection into a joint), ex vivo differentiated UC-MSCs, or UC-MSCs co-administered with other experimental cells or treatments (including other types of MSCs).

Study screening and selection, data extraction, and risk of bias assessments were all performed in duplicate by 2 independent reviewers (C.H., J.P.) using standardized forms. Discrepancies were resolved through discussion with a third team member (L.M.). Corresponding authors were emailed when data relevant to our systematic review was not reported in the included studies.

Data analysis

Data were extracted and analyzed as previously published.¹²^,¹⁹ Briefly, the following data were extracted using a standardized Excel spreadsheet: RCT and patient population characteristics, UC-MSC preparation and administration, risk of bias assessment, and safety outcome measures. Safety outcomes were evaluated according to the following prespecified adverse event categories: (1) fever within 24 h of study product administration, (2) non-fever acute infusional toxicity within 24 h of study product administration, (3) infection, (4) death, (5) malignancy/ectopic tissue formation, (6) thrombotic/thromboembolic events (arterial and venous), and (7) mycotic aneurysms. The adverse event data were extracted at the longest follow-up point; if a follow-up publication to an included study provided updated results, only these results were incorporated in the analysis. Adverse event data from RCTs with more than one UC-MSC study arm (eg, dose escalation trials) were combined into one UC-MSC study group for analysis. Prespecified adverse events were pooled and meta-analyzed using OpenMetaAnalyst (Windows 10). Data were analyzed using DerSimonian-Laird random effects models with a correction factor of 0.5 added to both arms for studies with 0 counts. Pooled events were described using relative risks (RR) and 95% confidence intervals (CI). Sensitivity analyses for all adverse events were performed using the Mantel–Haenszel random effects model since the DerSimonian–Laird approach may be problematic for sparse data.²⁰

We captured all SAEs reported in the included studies (both related to our prespecified adverse events and other SAEs). We also reported on their relatedness to the treatment and captured the number of studies stopped early due to safety concerns. The quality of adverse event reporting was captured using the CONSORT approach²¹ and UC-MSC characterization was described according to the Dominici criteria (MSC tri-lineage differentiation potential, cell surface markers, and adherence to plastic).²²

Heterogeneity between the included studies was evaluated using the I² statistic and P-value from the χ² test. Subgroup analyses were also conducted for each prespecified adverse event category according to the different patient populations (cardiovascular, neurological, oncological/hematological, endocrine, renal, liver, respiratory, immune-deficient/inflammatory, and other) and UC-MSC preparation type (fresh, cryopreserved, unclear). Two additional subgroups explored post hoc were duration of follow-up time (≤1 month, 2-12 months, >12 to 24 months, >24 months) and dose frequency (1 dose, >1 dose, unclear). No adjustments for multiple comparisons were made for these subgroup analyses as they were considered exploratory.

Post hoc, the presence of publication bias for the prespecified adverse event mortality (reported in 27 studies) was examined through visual inspection of a funnel plot and by the Egger regression test.²³

Risk of bias

Risk of bias analysis was conducted according to the Cochrane Collaboration methods.²⁴

Results

A total of 9160 studies were identified in our search for a total of 42 included RCTs (n = 2280 patients) (Table 1 and Figure 1).^25–66 Of the included studies, 7 were follow-up reports to an included study.⁴⁰^,⁴²^,⁴⁹^,⁵⁰^,⁵³^,⁵⁴^,⁶¹ Twenty of the included RCTs (47.6%) were multi-center²⁵^,²⁸^,^30–33^,³⁷^,³⁸^,⁴²^,⁴⁴^,⁴⁵^,⁵⁰^,⁵¹^,^54–57^,^60–62 and 22 were single center (52.4%).²⁶^,²⁷^,²⁹^,^34–36^,^39–41^,⁴³^,^46–49^,⁵²^,⁵³^,⁵⁸^,⁵⁹^,^63–66 The RCTs were conducted in 9 different countries with 30 (71.4%) conducted in the People’s Republic of China (PRC).²⁷^,^29–32^,^34–38^,⁴²^,⁴³^,^47–53^,^56–66 Sample sizes ranged from 13 to 250 patients (65.0 ± 50.5, mean ± SD). Seven RCTs (16.7%) had follow-up durations of ≤1 month,^39–41^,⁴⁴^,⁵¹^,⁵³^,⁶⁵ 23 (54.8%) with 2-12 months,^25–28^,²⁹^,³⁰^,³³^,³⁸^,⁴³^,⁴⁵^,⁴⁶^,^48–50^,^54–56^,⁵⁸^,⁵⁹^,^62–64^,⁶⁶ 7 (16.7%) with 13-24 months,³¹^,³⁴^,³⁵^,³⁷^,⁴²^,⁴⁷^,⁵⁷ and 5 (11.9%) with >24 months follow-up.³²^,³⁶^,⁵²^,⁶⁰^,⁶¹

Table 1.

Characteristics of included randomized controlled trials.

Source	Country	Patient population (sample size)	Single-center vs multi-center (number of centers)	Intervention (MSC source, MSC dose)	UC-MSC preparation	Control comparison (control, number of infusions)	Follow-up duration (months)^a	Patients randomized^b (n [% male])		Age (mean ± SD, years)^c
Source	Country	Patient population (sample size)	Single-center vs multi-center (number of centers)	Intervention (MSC source, MSC dose)	UC-MSC preparation	Control comparison (control, number of infusions)	Follow-up duration (months)^a	T	C	T	C
Cardiovascular
Gao et al.2015	PRC	Acute ST-elevation myocardial infarction (116)	Multi-center (11)	Unmatched allogeneic UC-MSCs, 6 × 10⁶ cells	Fresh	Saline with heparin, 1	18	58 (95)	58 (88)	57.3 ± 1.3	56.7 ± 1.7
Zhao et al., 2015	PRC	Chronic systolic heart failure (59)	Single-center	Unmatched allogeneic UC-MSCs, NR	Fresh	Drug therapy alone, 1	6	30 (80)	29 (66)	52.9 ± 16.3	53.2 ± 11.5
Bartolucci et al., 2016/2017	Chile	Stable heart failure (30)	Multi-center (2)	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells	Thaw-cultured fresh	Placebo, 1	12	15 (80.0)	15 (93.3)	57.33 ± 10.05	57.20 ± 11.64
Neurological
Xie et al., 2016	PRC	Encephalopathy (22)	Single-center	Unmatched allogeneic UC-MSCs, 1 × 10⁸ cells × 3 infusions	Fresh	Saline, 3	6	12 (67)	10 (60)	58.0 ± 7.4	63.3 ± 6.11
Oncological/hematological
Gao et al., 2016	PRC	Stem cell transplantation for hematologic malignancy (124)	Multi-center (5)	Unmatched allogeneic UC-MSCs, 3 × 10⁷ cells × 4 infusions	Fresh	Saline, 4	51 (24-70)	62 (47)	62 (48)	NR	NR
Fu et al., 2024	PRC	Steroid-refractory acute graft-versus-host disease (130)	Multi-center (3)	Unmatched allogeneic UC-MSCs + basiliximab, 1 × 10⁶ cells/kg × 4 infusions^d	Fresh	Basiliximabalone, NA	12	65 (56.9)	65 (47.7)	33 (18-68)	31 (18-62)
Huang et al., 2024	PRC	Acute leukemia (148)	Multi-center (5)	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 4 infusions	NR	Standard care, NA	24	74 (60.8)	74 (60.8)	28 (18-60)	28 (18-56)
Jiang et al., 2024	PRC	Steroid-refractory acute graft-versus-host disease (78)	Multi-center (7)	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 8 infusions^e	Cryopreserved	Placebo, 8	4	40 (62.5)	38 (55.3)	37.5 (17-62)	38.5 (13-60)
Yao et al., 2025	PRC	Graft-versus-host disease prevention for haploidentical hematopoietic stem cell transplantation (192)	Multi-center (3)	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 8 infusions^e	Cryopreserved	Regular prophylaxis, NA	36	96 (54.17)	96 (65.62)	Median = 37.0, IQR = 27.00-46.25	Median = 33.0, IQR = 22.75-46.00
Endocrine
Hu et al., 2013	PRC	Type 1 diabetes mellitus (29)	Single-center	Unmatched allogeneic UC-MSCs, (2.6 ± 1.2) × 10⁷ cells × 2 infusions	Fresh	Saline, 2	24	15 (60)	14 (57)	17.6 ± 8.7	18.2 ± 7.9
Hu et al., 2016	PRC	Type 2 diabetes mellitus (61)	Single-center	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg	Fresh	Saline, 1	36	31 (55)	30 (53)	52.43 ± 4.88	53.21 ± 8.22
Carlsson et al., 2023	Sweden	Type 1 diabetes (15)	Single-center	Unmatched allogeneic UC-MSCs, 200 × 10⁶ cells	Cryopreserved	Placebo, 1	12	10 (60)	5 (40)	31 ± 4	31 ± 9
Lian et al., 2023	PRC	Type 2 diabetes mellitus (34)	Single-center	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 3 infusions	Cryopreserved	Placebo, 3	6	24 (83.3)	10 (80)	52.0 (46.0-56.0)	49.0 (44.0-58.5)
Renal disease
Sun et al., 2018	PRC	Renal allograft (42)	Multi-center (3)	Unmatched allogeneic UC-MSCs, 2 × 10⁶ cells/kg then 5 × 10⁶ cells	Fresh	Standard treatment, NA	12	21 (67)	21 (52)	40.8 ± 9.2	47.1 ± 10.2
Liver disease
Shi et al., 2012	PRC	Acute-on-chronic liver failure (43)	Single-center	Unmatched allogeneic UC-MSCs, 0.5 × 10⁶ cells/kg/infusion × 3 infusions	Fresh	Saline, 3	18	24 (83)	19 (79)	40 (24-59)	45 (26-62)
Shi et al., 2017	PRC	First cadaveric liver transplantation (27)	Single-center	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg	Fresh	Standard treatment, NA	6	14 (92.9)	13 (92.3)	57 ± 12	55 ± 11
Shi M et al. 2021	PRC	Hepatitis B and decompensated liver cirrhosis (250)	Single-center	Unmatched allogeneic UC-MSCs, 0.5 × 10⁶ cells/kg × 3 infusions	Fresh	Conventional treatment, NA	75	125 (86.5)	125 (87.0)	48 (21-65)	47 (19-65)
Respiratory disease
Shu et al., 2020	PRC	COVID-19 (41)	Single center	Unmatched allogeneic UC-MSCs, 2 × 10⁶ cells/kg	NR	Standard care, NA	1	12 (66.67)	29 (55.17)	61.00 ± 17.87	57.86 ± 15.79
Dilogo et al., 2021	Indonesia	COVID-19 (40)	Multi-center (4)	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg	NR	Saline, 1	2	20 (75)	20 (75)	NR^f	NR^f
Feng et al., 2021^g	PRC	COVID-19 (41)	Single center	Unmatched allogeneic UC-MSCs, 2 × 10⁶ cells/kg	NR	Standard care, NA	3	12 (50)	29 (45)	50.50 (median = 39.00, IQR = 72.75)	51.00 (median = 43.25, IQR = 63.50)
Lanzoni et al., 2021	USA	COVID-19/ARDS (24)	Single-center	Unmatched allogeneic UC-MSCs, 100 ± 20 × 10⁶ × 2 infusions	Cryopreserved	Vehicle (human serum albumin and heparin), 2	1	12 (41.7)	12 (66.7)	58.58 ± 15.93	58.83 ± 11.61
Shi L et al., 2021	PRC	COVID-19 (101)	Multi-center (2)	Unmatched allogeneic UC-MSCs, 4 × 10⁷ cells × 3 infusions	Cryopreserved	Saline, 3	1	66 (56.92)	35 (54.29)	60.72 ± 9.14	59.94 ± 7.79
Zhu et al. 2021	PRC	COVID-19 (58)	Single-center	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg	Fresh	Placebo, 1	1	29 (41.4)	29 (34.5)	64 (54.5-68)	66 (59.5-69.5)
Kaffash Farkhad et al., 2022 (1)	Iran	COVID-19/ARDS (20)	Single-center	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 3 infusions	Fresh	Standard care, NA	17 days	10 (70)	10 (60)	NR^h	NR^h
Kaffash Farkhad et al., 2022 (2)ⁱ	Iran	COVID-19/ARDS (20)	Single-center	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 3 infusions	Fresh	Standard care, NA	17 days	10 (70)	10 (60)	NR^h	NR^h
Monsel et al., 2022	France	COVID-19/ARDS (47)	Multi-center (10)	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 3 infusions	Cryopreserved	Saline, 3	1	22 (81)	25 (83.3)	64.0 ± 10.4	63.2 ± 11.4
Rebelatto et al., 2022	Brazil	COVID-19 (17)	Single-center	Unmatched allogeneic UC-MSCs, 5 × 10⁵ cells/kg × 3 infusion	Thaw-cultured fresh	Placebo, 3	4	11 (72.7)	6 (66.6)	53 ± 15.3	61.7 ± 9.7
Shi and Feng et al., 2022^j	PRC	COVID-19 (41)	Single-center	Unmatched allogeneic UC-MSCs, 2 × 10⁶ cells/kg	NR	Standard care, NA	12	12 (50)	29 (41.18)	50.50 (median = 39.00, IQR = 72.75)	52.00 (median = 45.00, IQR = 63.00)
Shi and Wang et al., 2022^k	PRC	COVID-19 (101)	Multi-center (2)	Unmatched allogeneic UC-MSCs, 4 × 10⁷ cells × 3 infusions	Cryopreserved	Placebo, 3	12	66 (56.92)	35 (54.29)	60.72 ± 9.14	59.94 ± 7.79
Gorman et al., 2023	UK	COVID-19/ARDS (60)	Multi-center (12)	Unmatched allogeneic UC-MSCs, 400 × 10⁶ cells	Cryopreserved	Placebo, 1	3	30 (80)	30 (69)	58.4 ± 9.2	58.4 ± 12.5
Li et al., 2023^l	PRC	COVID-19 (101)	Multi-center (2)	Unmatched allogeneic UC-MSCs, 4 × 10⁷ cells × 3 infusions	Cryopreserved	Placebo, 3	24	66 (56.92)	35 (54.29)	60.72 ± 9.14	59.94 ± 7.79
Pochon et al., 2023	France	COVID-19/ARDS (30)	Multi-center (2)	Unmatched allogeneic UC-MSCs, 1 infusion of 1 × 10⁶ cells/kg and 2 infusions of 0.5 × 10⁶ cells/kg	Cryopreserved	Placebo, 3	3	15 (87)	15 (47)	61 (median = 49, IQR = 66)	66 (median = 61, IQR = 70)
Soetjahjo et al., 2023	Indonesia	COVID-19 (42)	Multi-center (3)	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 3 infusions	NR	Placebo, 3	3	21 (47.6)	21 (57.1)	56.10 ± 12.49	55.86 ± 10.17
Sitbon et al., 2024^m	France	COVID-19/ARDS (47)	Multi-center (10)	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 3 infusions	Cryopreserved	Saline, 3	12	22 (81)	25 (83.3)	64.0 ± 10.4	63.2 ± 11.4
Yuan et al., 2025ⁿ	PRC	COVID-19 (101)	Multi-center (2)	Unmatched allogeneic UC-MSCs, 4 × 10⁷ cells × 3 infusions	Cryopreserved	Saline, 3	36	66 (56.92)	35 (54.29)	60.72 ± 9.14	59.94 ± 7.79
Immune-deficient/auto-immune/inflammatory
Zhang et al., 2013	PRC	HIV-1 infection (13)	Multi-center (NR)	Unmatched allogeneic UC-MSCs, 0.5 × 10⁶ cells/kg × 3 infusions	Fresh	Saline, 3	12	7 (71)	6 (83)	30 (26-49)	38 (19-55)
Hu et al., 2015/2016	PRC	Ulcerative colitis (80)	Single-center	Unmatched allogeneic UC-MSCs, 0.5 × 10⁶ cells/kg × 2 infusions	Fresh	Saline, 2	24	40 (62)	40 (61)	42.9 ± 23.1	43.7 ± 28.7
Deng et al., 2017	PRC	Systemic lupus erythematosus (18)	Single-center	Unmatched allogeneic UC-MSCs, 2 × 10⁸ cells × 2 infusions	Cryopreserved	Placebo, 2	12	12 (8)	6 (0)	29 ± 10	29 ± 7
Zhang et al., 2018	PRC	Crohn’s disease (82)	Single-center	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 4 infusions	Cryopreserved	Standard treatment, NA	12	41 (58.5)	41 (63.4)	34.3 (21-44)	32.7 (20-41)
Yang et al., 2018	PRC	Rheumatoid arthritis (105)	Single-center	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg	Thaw-cultured fresh	Placebo, 1	11	Response group 28 (25) No-response group 24 (21)	53 (19)	Response group 50.7 No-response group 51.2	49.8
Wang et al., 2021	PRC	AIDS (72)	Multi-center (NR)	Unmatched allogeneic UC-MSCs (high and low dose), < 0.5 × 10⁶ cells/kg or 1.5 × 10⁶ cells/kg × 6 infusions	NR	Placebo, 1	22	High dose 24 (79.17) Low dose 24 (79.17)	24 (79.17)	High dose 42.0 (33.3-48.0) Low dose 42.5 (38.0-45.8)	41.5 (35.5-48.8)
Other
Zhu et al., 2024	PRC	Frailty (30)	Single-center	Unmatched allogeneic UC-MSCs, 1 × 10⁶ cells/kg × 2 infusions	Fresh	Placebo, 2	6	15 (33.33)	15 (46.67)	67.27 ± 5.23	69.27 ± 5.02

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The longest follow-up timepoint is reported in this table.

Refers to the total number of patients randomized in each RCT, but the number of patients included in the final analyses may differ. These values reflect the number of patients included for analysis in our study (eg, treatment groups given UC-MSCs + exosomes or UC-MSCs + BM-MSCs were excluded).

Some studies reported age as median (range) in years.

UC-MSCs were given once a week for 4 weeks and if the patient achieves partial response after 4 weeks, MSC infusions are repeated for another 4 weeks.

UC-MSCs were given twice a week for 4 weeks and if the patient achieves partial response after 4 weeks, MSC infusions are repeated for another 4 weeks.

Age was reported in categories of <40 years, 40-60 years, and >60 years. Therefore, the age in years ± SD could not be determined.

Three-month follow-up study by Shu et al.⁵³

The age range (ie, 60-69) was reported for each patient—therefore, the age in years ± SD could not be determined.

ⁱ

Follow-up study by Kaffash Farkhad et al.³⁹

One-year follow-up study by Shu et al.⁵³

One-year follow-up study to Shi et al.⁵¹

Two-year follow-up study by Shi et al.⁵¹

One-year follow-up study by Monsel et al.⁴⁴

ⁿ

Three-year follow-up study by Shi et al.⁵¹

Abbreviations: AIDS = acquired immunodeficiency syndrome; ARDS = acute respiratory distress syndrome; C = control; COVID-19 = coronavirus disease 2019; HIV = human immunodeficiency virus; MSCs = mesenchymal stromal cells; NA = not applicable. NR = not reported; PRC = People’s Republic of China; RCT = randomized controlled trials; T = treatment; UK = United Kingdom; UC = umbilical cord.

The included RCTs consisted of diverse patient populations, including cardiovascular (3 studies, n = 205 patients),²⁵^,³¹^,⁶⁴ neurological (1 study, n = 22 patients),⁵⁸ oncological/hematological (5 studies, n = 672 patients),³⁰^,³²^,³⁷^,³⁸^,⁶⁰ endocrine (4 studies, n = 139 patients),²⁶^,³⁴^,³⁶^,⁴³ renal (1 study, n = 42 patients),⁵⁶ hepatic (3 studies, n = 320 patients),⁴⁷^,⁴⁸^,⁵² respiratory (18 studies, n = 480 patients),²⁸^,²⁹^,³³^,^39–42^,^44–46^,⁴⁹^,^51–55^,⁶¹^,⁶⁵ immune-deficient or inflammatory diseases (6 studies, n = 370 patients),²⁷^,³⁵^,⁵⁷^,⁵⁹^,⁶²^,⁶³ and other diseases (1 study, n = 30 patients).⁶⁶

Twenty RCTs (47.6%) studied fresh UC-MSCs²⁵^,^30–32^,^34–36^,³⁹^,⁴⁰^,^46–48^,⁵²^,⁵⁶^,⁵⁸^,⁵⁹^,⁶²^,^64–66; 3 of which studied a cryopreserved cell product that was subsequently thawed and cultured prior to administration as a fresh product,²⁵^,⁴⁶^,⁵⁹ 15 (35.7%) used cryopreserved UC-MSCs,²⁶^,²⁷^,³³^,³⁸^,^41–45^,⁵⁰^,⁵¹^,⁵⁴^,⁶⁰^,⁶¹^,⁶³ and in 7 (16.7%), the UC-MSC preparation was unclear.²⁸^,²⁹^,³⁷^,⁴⁹^,⁵³^,⁵⁵^,⁵⁷ In terms of the dose of UC-MSCs, 12 RCTs (28.6%) administered a single dose of UC-MSCs,²⁵^,²⁶^,²⁸^,²⁹^,³¹^,³³^,³⁶^,⁴⁸^,⁴⁹^,⁵³^,⁵⁹^,⁶⁵ 29 (69.0%) administered more than one dose of UC-MSCs,²⁷^,³⁰^,³²^,³⁴^,³⁵^,^37–47^,^50–52^,^54–58^,^60–63^,⁶⁶ and the number of doses was not reported in one RCT (2.4%).⁶⁴

Eleven RCTs (26.2%) reported on all 3 Dominici criteria,²⁵^,³²^,⁴²^,⁴⁷^,⁴⁸^,⁵⁰^,⁵¹^,⁵⁹^,^61–63 41 RCTs (97.6%) reported on at least one of the criteria,^25–64^,⁶⁶ and one study did not report on any criteria.⁶⁵ Twenty-five RCTs (59.5%) reported on cell viability^25–27^,³⁰^,³¹^,³³^,³⁷^,^39–46^,⁴⁸^,^50–52^,⁵⁴^,^58–61^,⁶⁶ and one RCT (2.4%) reported on UC-MSC potency.³⁸ For studies that determined the UC-MSC dose per kilogram of patient body weight, the dose ranged from 5 × 10⁵ to 2 × 10⁶ cells/kg; for studies that specified a final cell dose, the dose ranged from 1 × 10⁶ to 400 × 10⁶ cells. Additional detail on the UC-MSC preparation and administration can be found in Supplementary Table S1.

Risk of bias assessment

Of the 42 RCTs included, 14 (33.3%) were considered as low-risk for all 6 risk of bias assessment domains (Table 2)²⁵^,²⁶^,²⁸^,³¹^,³³^,⁴¹^,⁴⁵^,⁴⁶^,⁵⁰^,⁵¹^,⁵⁴^,⁵⁵^,⁵⁷^,⁶¹ and a further 7 RCTs (16.7%) were rated as low-risk for 5 of the 6 risk of bias assessment domains.²⁷^,³⁰^,³²^,³⁴^,³⁵^,³⁷^,³⁸ Twenty-six RCTs (61.9%) concealed the allocation lists,^25–28^,^30–35^,³⁷^,³⁸^,⁴¹^,⁴⁵^,⁴⁶^,^50–52^,^54–57^,⁶⁰^,⁶¹^,⁶³^,⁶⁶ 21 (50.0%) were double-blinded,^25–28^,^31–34^,³⁸^,⁴¹^,⁴²^,^44–46^,⁵⁰^,⁵¹^,⁵⁴^,⁵⁵^,⁶¹^,⁶⁶ and 3 (7.1%) had an open-label intervention but blinded outcome measures.²⁹^,³⁰^,⁴⁸ In evaluating other potential sources of biases, we found that 39 RCT (92.9%) trial protocols were registered on either clinicaltrials.gov or another regional registration program^25–33^,³⁵^,^37–63^,⁶⁵^,⁶⁶ and 20 (47.6%) reported an a priori sample size calculation.²⁶^,²⁸^,^30–33^,³⁷^,⁴¹^,⁴⁴^,⁴⁵^,^50–52^,⁵⁴^,⁵⁶^,⁵⁷^,⁶⁰^,⁶¹^,⁶³^,⁶⁶

Table 2.

Risk of bias assessments.

Author, Year	Selection bias		Performance bias			Reporting bias		Other bias
Author, Year	1—Random sequence generation	2—Allocation concealment	3—ROB due to blinding: patients & personnel	4—ROB due to blinding: outcome assessor	5—Attrition: incomplete outcome data	6—Selective outcome reporting	Registered Protocol (Y/N)	A priori sample size calculation for primary outcome in methods	Industry or biotech-sponsored
Cardiovascular
Gao et al., 2015
Zhao et al., 2015
Bartolucci et al., 2016/2017
Neurological
Xie et al., 2016
Oncological/hematological
Gao et al., 2016
Fu et al., 2024
Huang et al., 2024
Jiang et al., 2024
Yao et al., 2025
Endocrine
Hu et al., 2013
Hu et al., 2016
Carlsson et al., 2023
Lian et al., 2023
Renal disease
Sun et al., 2018
Liver disease
Shi et al., 2012
Shi et al., 2017
Shi M et al. 2021
Respiratory disease
Shu et al., 2020
Dilogo et al., 2021
Feng et al., 2021
Lanzoni et al., 2021
Shi L et al., 2021
Zhu et al. 2021
Kaffash Farkhad et al., 2022 (1)
Kaffash Farkhad et al., 2022 (2)
Monsel et al., 2022
Rebelatto et al., 2022
Shi and Feng et al., 2022
Shi and Wang et al., 2022
Gorman et al., 2023
Li et al., 2023
Pochon et al., 2023
Soetjahjo et al., 2023
Sitbon et al., 2025
Yuan et al., 2025
Immune-deficient/auto-immune/inflammatory
Zhang et al., 2013
Hu et al., 2015/2016
Deng et al., 2017
Zhang et al., 2018
Yang et al., 2018
Wang et al., 2021
Other
Zhu et al., 2024

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Abbreviation: ROB = risk of bias.

Green = low risk of bias; yellow = unclear risk of bias; red = high risk of bias.

Safety

A priori plans to monitor safety were reported in 35 RCTs (83.3%) (Supplementary Table S2).²⁵^,²⁶^,²⁸^,^30–36^,³⁸^,³⁹^,^41–47^,^49–52^,^54–57^,^59–66 Twenty-one (50.0%) of these also reported an a priori description of the adverse events to be monitored²⁵^,^30–33^,³⁶^,^41–45^,⁴⁷^,⁴⁹^,⁵¹^,⁵²^,⁵⁴^,⁵⁶^,⁵⁷^,⁶²^,⁶⁵^,⁶⁶ and 34 RCTs (81.0%) provided an a priori description of the follow-up duration or frequency for adverse events.²⁵^,²⁶^,²⁸^,^30–36^,³⁸^,³⁹^,^41–47^,^49–52^,^54–57^,⁵⁹^,^61–66 In terms of overall safety, no included RCTs reported any SAEs related to the study treatment and no RCTs were stopped early due to safety concerns.

The frequency of each prespecified adverse event category (fever, non-fever acute infusional toxicity, infection, death, malignancy/ectopic tissue formation, thrombotic/thromboembolic events, and mycotic aneurysms) is presented in Supplementary Table S3 and summarized in forest plots in Figure 2A-G.

A total of 15 RCTs (n = 954 patients) reported the occurrence of fever as adverse events within 24 hours of study product administration.²⁵^,³³^,³⁵^,³⁶^,³⁹^,⁴³^,⁴⁷^,⁵²^,⁵³^,⁵⁶^,⁵⁸^,⁵⁹^,⁶²^,⁶³^,⁶⁵ In a pooled meta-analysis, there was a significant increased risk of fever for the UC-MSC group (treatment group) compared to the control group (RR = 2.34, 95% CI = 1.02-5.35, P = .04, I² = 0%, Figure 2A).

A total of 21 RCTs (n = 1511 patients) reported the occurrence of non-fever acute infusional toxicity adverse events (eg, allergic reactions, chest pain, headaches, significant changes to vital signs etc.).²⁵^,²⁷^,²⁸^,^30–32^,³⁵^,³⁸^,³⁹^,⁴¹^,⁴⁴^,⁴⁶^,⁴⁸^,⁵²^,⁵³^,^56–58^,⁶⁰^,⁶³^,⁶⁴ In a pooled meta-analysis, there was no signal for harm for non-fever acute infusional toxicity adverse events for the UC-MSC group compared to the control group (RR = 1.14, 95% CI = 0.53-2.45, P = .74, I² = 0%, Figure 2B).

A total of 10 RCTs (n = 613 patients) reported the occurrence of infection.²⁷^,³¹^,³⁶^,⁴⁸^,⁵⁰^,⁵⁶^,⁵⁷^,⁵⁹^,⁶²^,⁶⁵ In a pooled meta-analysis, there was no signal for harm for infection for the UC-MSC group compared to the control group (RR = 0.73, 95% CI = 0.32-1.66, P = .45, I² = 0%, Figure 2C).

A total of 27 RCTs (n = 1900 patients) reported the occurrence of death.^25–28^,^30–33^,^35–39^,⁴¹^,^45–47^,⁴⁹^,⁵²^,^54–56^,⁵⁸^,⁶⁰^,⁶¹^,⁶⁴^,⁶⁵ In a pooled meta-analysis, there was no signal for harm for death for the UC-MSC group compared to the control group (RR = 0.77, 95% CI = 0.60-0.99, P = .04, I² = 22.61%, Figure 2D).

A total of 9 RCTs (n = 734 patients) reported the occurrence of malignancy/ectopic tissue formation.²⁵^,²⁶^,³¹^,³⁸^,⁵²^,⁵⁷^,⁶¹^,⁶²^,⁶⁴ In a pooled meta-analysis, there was no signal for harm for malignancy/ectopic tissue formation events for the UC-MSC group compared to the control group (RR = 0.63, 95% CI = 0.36-1.09, P = .10, I² = 0%, Figure 2E).

A total of 10 RCTs (n = 496 patients) reported the occurrence of thrombotic/thromboembolic events.²⁵^,²⁷^,²⁹^,³¹^,³⁶^,³⁹^,⁴⁵^,⁴⁷^,⁵⁶^,⁶³ In a pooled meta-analysis, there was no signal for harm for thrombotic/thromboembolic adverse events for the UC-MSC group compared to the control group (RR = 0.89, 95% CI = 0.38-2.05, P = .78, I² = 0%, Figure 2F).

A total of 3 RCTs (n = 132 patients) reported the occurrence of mycotic aneurysm events.²⁵^,³⁵^,⁵⁸ In a pooled meta-analysis, there was no signal for harm for mycotic aneurysm events for the UC-MSC group compared to the control group (RR = 0.95, 95% CI = 0.10-8.79, P = .96, I² = 0%, Figure 2G).

Subgroup analyses for each prespecified adverse event category are presented in Table 3. An increased risk of fever was found for the liver disease population (2 RCTs, n = 306 patients, RR = 10.15, 95% CI = 1.29-79.95) and when more than one dose of UC-MSCs was administered (9 RCTs, n = 599, RR = 3.78, 95% CI = 1.31-10.89). None of the subgroup analyses demonstrated harm signals for non-fever infusional toxicity, infection, death, malignancy/ectopic tissue formation, thrombotic/thromboembolic, or mycotic aneurysms adverse events.

Table 3.

Summary of subgroup analyses.

Subgroup (Total # of RCTs)	Infusional toxicity—fever		Infusional toxicity—non-fever		Infection		Death		Malignancy/ectopic tissue formation		Thrombotic/thromboembolic events		Aneurysms
Subgroup (Total # of RCTs)	# of RCT	RR (95% CI)	# of RCTs	RR (95% CI)	# of RCT	RR (95% CI)	# of RCT	RR (95% CI)	# of RCT	RR (95% CI)	# of RCT	RR (95% CI)	# of RCTs	RR (95% CI)
Patient population
Cardiovascular (3)	1	1.00 (0.02-47.38)	3	1.58 (0.20-12.56)	1	3.00 (0.12-72.15)	3	0.37 (0.11-1.22)	3	0.99 (0.18-5.55)	2	0.62 (0.08-4.88)	1	1.00 (0.02-47.38)
Neurological (1)	1	0.85 (0.02-39.24)	1	0.85 (0.02-39.24)	NA	NA	1	0.85 (0.02-39.24)	NA	NA	NA	NA	1	0.85 (0.02-39.24)
Oncological/hematological (5)	NA	NA	4	0.99 (0.14-6.95)	NA	NA	5	0.91 (0.55-1.51)	1	0.95 (0.02-46.77)	NA	NA	NA	NA
Endocrine (4)	2	2.43 (0.25-24.00)	NA	NA	1	0.97 (0.02-47.32)	2	0.72 (0.05-10.90)	1	1.64 (0.08-34.28)	1	0.97 (0.02-47.32)	NA	NA
Renal disease (1)	1	1.00 (0.02-48.19)	1	1.00 (0.02-48.19)	1	0.50 (0.14-1.74)	1	0.20 (0.01-3.93)	NA	NA	1	1.00 (0.07-14.95)	NA	NA
Liver disease (3)	2	10.15 (1.29-79.95)	2	0.97 (0.06-15.02)	1	0.19 (0.01-3.56)	2	0.41 (0.22-0.76)	1	0.57 (0.30-1.06)	1	1.32 (0.03-64.26)	NA	NA
Respiratory disease (18)	4	0.87 (0.19-4.06)	6	1.39 (0.41-4.64)	2	1.00 (0.11-8.80)	11	0.79 (0.57-1.08)	1	0.53 (0.03-8.22)	3	1.15 (0.36-3.66)	NA	NA
Immune/inflammatory (6)	4	4.27 (0.90-20.37)	4	0.72 (0.10-5.00)	4	1.23 (0.21-7.17)	2	1.34 (0.12-14.96)	2	0.67 (0.04-10.15)	2	0.35 (0.03-3.85)	1	1.00 (0.02-49.20)
Other (1)	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
UC-MSC preparation
Fresh (20)	11	2.09 (0.78-5.65)	11	1.17 (0.40-3.41)	7	0.57 (0.23-1.44)	14	0.69 (0.51-0.93)	5	0.60 (0.34-1.07)	6	0.71 (0.20-2.55)	3	0.95 (0.10-8.79)
Cryopreserved (15)	3	3.15 (0.62-15.98)	6	0.95 (0.24-3.68)	2	2.69 (0.33-21.66)	8	0.95 (0.52-1.73)	2	1.33 (0.12-14.65)	3	0.98 (0.31-3.10)	NA	NA
Unclear (7)	1	2.31 (0.05-110.14)	4	1.48 (0.24-9.21)	1	0.51 (0.01-24.96)	5	0.67 (0.48-0.93)	2	0.70 (0.04-10.99)	1	2.31 (0.05-110.14)	NA	NA
Post hoc subgroup analyses
Duration of follow-up time
≤1 month (7)	3	0.84 (0.11-6.33)	4	1.95 (0.45-8.42)	1	0.33 (0.01-7.86)	3	0.45 (0.13-1.60)	NA	NA	1	0.33 (0.02-7.32)	NA	NA
2-12 months (23)	8	2.56 (0.84-7.79)	11	0.95 (0.32-2.80)	6	0.69 (0.27-1.77)	15	0.97 (0.71-1.33)	5	1.09 (0.25-4.84)	6	0.93 (0.35-2.47)	2	0.92 (0.06-13.97)
>12 to 24 months (7)	2	3.28 (0.31-35.16)	3	0.80 (0.08-7.57)	2	1.48 (0.13-17.31)	4	0.69 (0.43-1.09)	2	0.80 (0.08-7.54)	2	1.10 (0.12-10.34)	1	1.00 (0.02-49.20)
>24 months (5)	2	5.31 (0.39-71.88)	3	1.00 (0.10-9.55)	1	0.97 (0.02-47.32)	5	0.50 (0.24-1.03)	2	0.56 (0.30-1.04)	1	0.97 (0.02-47.32)	NA	NA
Dose frequency
1 dose (12)	6	1.10 (0.29-4.14)	5	1.17 (0.21-6.58)	5	0.65 (0.14-2.88)	8	0.65 (0.43-0.98)	3	1.15 (0.23-5.83)	4	0.85 (0.16-4.43)	1	1.00 (0.02-47.38)
≥1 dose (29)	9	3.78 (1.31-10.89)	15	1.05 (0.44-2.55)	5	0.76 (0.28-2.07)	18	0.82 (0.59-1.14)	5	0.58 (0.32-1.04)	6	0.90 (0.34-2.38)	2	0.92 (0.06-14.14)
Unclear (1)	NA	NA	1	2.90 (0.12-68.50)	NA	NA	1	0.28 (0.06-1.22)	1	0.97 (0.02-47.22)	NA	NA	NA	NA

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Abbreviations: RCT = randomized controlled trial; RR = relative risk; 95% CI = 95% confidence interval; NA = not applicable.

Visual inspection of the funnel plot and Egger regression test did not suggest evidence of publication bias for mortality (intercept = −0.40, 95% CI = −1.12 to 0.32, P = .285) (Supplementary Figure S1).

Sensitivity analyses using the Mantel–Haenszel approach found similar pooled estimates of effect with overlapping confidence intervals for all adverse events (Supplementary Table S4).

A summary of the pooled point estimates and 95% CIs for the prespecified adverse event categories from our prior systematic review of all MSC sources (n = 55), a subgroup analysis of UC-MSCs from that review (n = 15), the new UC-MSC studies added in our current review (n = 27), and all UC-MSCs RCTs (n = 42) is presented in Table 4. There continues to be no signals for harm related to the development of non-fever acute infusional toxicity, infection, death, malignancy/ectopic tissue formation, or thrombotic/thromboembolic events.

Table 4.

Comparison of adverse events between our 2019 systematic review and our updated systematic review.

Adverse events	2019 SR (all MSC sources)		2019 SR (UC-MSC subgroup)		Updated UC-MSC SR (new studies added since 2019)		Updated UC-MSC SR (all UC-MSC studies)
Adverse events	# of RCTs	Findings (RR, 95% CI)	# of RCTs^a	Findings (RR, 95% CI)	# of RCTs	Findings (RR, 95% CI)	# of RCTs	Findings (RR, 95% CI)
Infusional toxicity—fever	19/55	2.48 (1.27-4.86)	9/15	2.73 (0.89-8.41)	6/27	1.95 (0.53-7.11)	15/42	2.34 (1.02-5.35)
Infusional toxicity—non-fever	32/55	1.16 (0.70-1.91)	10/15	1.07 (0.32-3.54)	11/27	1.19 (0.44-3.21)	21/42	1.14 (0.53-2.45)
Infection	27/55	0.99 (0.81-1.21)	7/15	0.70 (0.28-1.76)	3/27	0.85 (0.13-5.68)	10/42	0.73 (0.32-1.66)
Death	40/55	0.78 (0.65-0.94)	10/15	0.53 (0.28-1.00)	17/27	0.79 (0.56-1.11)	27/42	0.77 (0.60-0.99)
Malignancy or ectopic tissue formation	19/55	0.93 (0.60-1.45)	4/15	0.97 (0.20-4.65)	5/27	0.59 (0.33-1.07)	9/42	0.63 (0.36-1.09)
Thrombotic/thromboembolic events	24/55	1.14 (0.67-1.95)	7/15	0.66 (0.20-2.23)	3/27	1.15 (0.36-3.66)	10/42	0.89 (0.38-2.05)
Mycotic aneurysm	NA	NA	NA	NA	3/27	0.95 (0.10-8.79)	3/42	0.95 (0.10-8.79)

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Only 15/16 studies reported on adverse events because one was in abstract form only. Also, please note that the number of studies in this column may differ from our previous publication as there was an error that has now been corrected here.

Abbreviations: CI = confidence interval; MSC = mesenchymal stromal cells; NA = not applicable; RCT = randomized controlled trial; RR = relative risk; SR = systematic review; UC-MSC = umbilical-cord-derived mesenchymal stromal cells.

Discussion

In this systematic review, we identified 27 RCTs specific for UC-MSC (n = 1429 patients) in addition to the 15 UC-MSC RCTs from our previous review for a total of 42 included UC-MSC RCTs. With the exception of fever, there were no signals for harm for any of the prespecified adverse event categories, which is consistent with the results of our prior systematic review that evaluated all types of MSCs.¹²^,¹⁹ None of the studies that recorded fever events described the fevers as serious. Findings from this systematic review reinforce that UC-MSCs have a favorable short-term safety profile.

The included RCTs studied a heterogeneous group of disorders because our aim was to describe the totality of the evidence of adverse events that are potentially associated with UC-MSCs. The frequency and severity of the prespecified adverse events, including mortality, may be influenced by the patient population, differences in immune profiles, and other sources of heterogeneity; several sources of heterogeneity were explored in our subgroup analyses. We identified a significantly increased risk for fever for liver disease when more than one dose of UC-MSCs was administered. However, due to the multiple comparisons, the results of these subgroup analyses should be considered hypothesis-generating.

Although we did not detect harm signals for thrombotic/thromboembolic events or malignancy/ectopic tissue formation, the confidence intervals about these estimates remain wide and cross the null because these events are rare. Of the 42 included RCTs, only 10 reported on the occurrence of thrombotic/thromboembolic events. Four reported on malignancy/ectopic tissue formation at a follow-up duration of more than 12 months; however, malignancies may take longer to become clinically apparent. We encourage investigators to continue to report on these important events in their clinical trials and to have sufficient follow-up durations for their detection.

Continued reporting of the characterization of the UC-MSC therapy in RCTs is essential as it represents another source of heterogeneity that could explain differences in both efficacy and safety between trials. The use of a set of minimal criteria to define human MSC, such as the Dominici criteria, can help foster more meaningful comparisons.²² While 41/42 RCTs (97.6%) reported on at least one of the Dominici criteria in our review, only 11 of the RCTs (26.2%) reported on all 3, which is fewer than the 7/16 RCTs (43.8%) in our previous review. Cell viability and potency are 2 additional important measures. Twenty-five RCTs (59.5%) reported on cell viability (compared to 6/16 RCTs [37.5%] in our previous review); 7 reported viability at release, 7 before infusion, 8 at both release and infusion, and in 3 RCTs the time of measurement of viability was not clear. No studies in our previous review and only one in this updated review reported on a measure of UC-MSC potency or functionality. Recently, an international group of experts published reporting guidelines that include a set of 9 consensus criteria to define and characterize MSCs for reporting in clinical trials.⁶⁷ More strict adherence to the evolving consensus reporting standards should enhance the reproducibility of UC-MSC therapies and enable a more clear interpretation of efficacy and safety findings from RCTs.

The risk of bias of our included RCTs is also imperative to understanding the validity of the safety profile of UC-MSC therapy. Of the 42 RCTs included, 14 RCTs (33.3%) were rated as low-risk for all 6 risk of bias assessment domains in comparison to only 2/16 UC-MSC RCTs (12.5%) in our 2019 systematic review. While this represents progress, the majority of domains remained unclear in trials not meeting low-risk criteria. We continue to urge investigators to improve reporting of these key elements to allow more accurate assessment of internal validity.

As noted in our previous review, we found that a majority of authors continue to report an a priori plan to monitor for safety (83.3% vs 75.0%). Twenty-one RCTs reported on the occurrence of SAEs, but none were considered related to the study treatment. No trials were reported to end prematurely due to safety concerns suggesting that the administration of UC-MSC therapy continues to appear safe.

This updated systematic review and meta-analysis has several strengths. These include a prepublished and transparent search strategy, a clear and pre-defined list of adverse events that may be potentially relevant to UC-MSC administration, and full reporting on all SAEs identified regardless of their relatedness to the study treatment. One limitation of this review may be that published data in abstract form only were not included due to the limited information available in these texts. Secondly, in the pooled analyses of our prespecified adverse events, only incident adverse events were included. If the study reported on the number of adverse events instead, clarification was requested through email to the corresponding authors, but responses were not complete. These values were reported in supplementary data tables for readers to review.

Conclusion

In conclusion, our updated systematic review continues to indicate that UC-MSCs have a favorable short-term safety profile in heterogeneous patient populations. Our systematic analysis of prespecified adverse events did not identify any signal for harm other than acute fever, and no studies were stopped due to safety. We urge investigators to report on rare adverse events and those that require a longer follow-up duration for their detection like thromboses and thromboembolic events and malignancies, respectively, and to transparently report on the characterization of UC-MSCs using the recently reported consensus guidelines as well as risk of bias elements to have an optimal understanding of the safety profile of UC-MSC therapy.

Supplementary Material

szag029_Supplementary_Data

szag029_supplementary_data.docx^{(216.1KB, docx)}

Acknowledgments

We would like to acknowledge Risa Shorr, information specialist at the Ottawa Hospital Research Institute (OHRI), for her help in designing and conducting the systematic search strategy and Elham Sabri, statistician at the OHRI, for her assistance in conducting the statistical analyses.

Contributor Information

Christine Hum, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.

Jessica Poliwoda, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada.

Manoj Lalu, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada; Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada; Department of Anesthesiology and Pain Medicine, University of Ottawa, The Ottawa Hospital, Ottawa, ON, K1H 8L6, Canada.

Duncan J Stewart, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada; Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada.

Shirley H J Mei, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.

Keith R Walley, Department of Medicine, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, V6Z 1Y6, Canada.

John Marshall, Department of Surgery (Critical Care), St. Michael’s Hospital, University of Toronto, Toronto, ON, M5T 1P5, Canada.

Asher A Mendelson, Section of Critical Care Medicine, Department of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R3E 3P5, Canada.

Dean A Fergusson, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada; Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada.

Shane English, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada; Department of Medicine (Critical Care), The Ottawa Hospital, Ottawa Hospital Research Institute, Centre for Transfusion and Critical Care Research, Ottawa, ON, K1H 8L6, Canada; Department of Medicine (Division of Critical Care), University of Ottawa, Ottawa, ON, K1H 8L6, Canada.

Brent W Winston, Department of Critical Care, Medicine, and Biochemistry and Microbiology, University of Calgary, Calgary, AB, T2N 1N4, Canada.

John Granton, Department of Medicine (Critical Care), University of Toronto, Toronto, ON, M4N 3M5, Canada.

Claudia C dos Santos, Keenan Research Centre for Biomedical Science and Interdepartmental Division of Critical Care, St. Michael’s Hospital, University of Toronto, Toronto, ON, M5B 1W8, Canada.

Josee Champagne, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.

Lauralyn McIntyre, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada; Department of Medicine (Critical Care), The Ottawa Hospital, Ottawa Hospital Research Institute, Centre for Transfusion and Critical Care Research, Ottawa, ON, K1H 8L6, Canada; Department of Medicine (Division of Critical Care), University of Ottawa, Ottawa, ON, K1H 8L6, Canada.

Author contributions

Christine Hum: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. Jessica Poliwoda: collection and/or assembly of data, manuscript writing, final approval of manuscript. Manoj Lalu: conception and design, manuscript writing, and final approval of manuscript. Duncan J. Stewart: conception and design, manuscript writing, and final approval of manuscript. Shirley H.J. Mei: conception and design, manuscript writing, and final approval of manuscript. Keith R. Walley: manuscript writing and final approval of manuscript. John Marshall: manuscript writing and final approval of manuscript. Asher A. Mendelson: manuscript writing and final approval of manuscript. Dean A. Fergusson: conception and design, manuscript writing, and final approval of manuscript. Shane English: manuscript writing and final approval of manuscript. Brent W. Winston: manuscript writing and final approval of manuscript. John Granton: manuscript writing and final approval of manuscript. Claudia C. Dos Santos: manuscript writing and final approval of manuscript. Josee Champagne: administrative support, manuscript writing, and final approval of manuscript. Lauralyn McIntyre: conception and design, administrative support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript.

Christine Hum (Conceptualization [lead], Data curation [lead], Formal analysis [lead], Investigation [lead], Methodology [lead], Writing—original draft [lead], Writing—review & editing [lead]), Jessica Poliwoda (Data curation [supporting], Writing—original draft [supporting], Writing—review & editing [supporting]), Manoj Lalu (Conceptualization [supporting], Writing—original draft [supporting], Writing—review & editing [supporting]), Duncan J Stewart (Conceptualization [supporting], Writing—original draft [supporting], Writing—review & editing [supporting]), Shirley Hsin-Ju Mei (Conceptualization [supporting], Writing—original draft [supporting], Writing—review & editing [supporting]), Keith Walley (Writing—original draft [supporting], Writing—review & editing [supporting]), John Marshall (Writing—original draft [supporting], Writing—review & editing [supporting]), Asher A Mendelson (Writing—original draft [supporting], Writing—review & editing [supporting]), Dean Fergusson (Conceptualization [supporting], Writing—original draft [supporting], Writing—review & editing [supporting]), Shane English (Writing—original draft [supporting], Writing—review & editing [supporting]), Brent W. Winston (Writing—original draft [supporting], Writing—review & editing [supporting]), John Granton (Writing—original draft [supporting], Writing—review & editing [supporting]), Claudia C. Dos Santos (Writing—original draft [supporting], Writing—review & editing [supporting]), Josee Champagne (Project administration [supporting], Writing—original draft [supporting], Writing—review & editing [supporting]), and Lauralyn McIntyre (Conceptualization [lead], Data curation [lead], Formal analysis [lead], Methodology [lead], Project administration [lead], Supervision [lead], Writing—original draft [lead], Writing—review & editing [lead])

Supplementary material

Supplementary material is available at Stem Cells Translational Medicine online.

Funding

This study was funded by the Stem Cell Network (20160906).

Conflicts of interest

None declared.

Data availability

The data underlying this article are available in the article and in its online supplementary material.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

szag029_Supplementary_Data

szag029_supplementary_data.docx^{(216.1KB, docx)}

Data Availability Statement

The data underlying this article are available in the article and in its online supplementary material.

[szag029-B1] 1. Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant. 2011;20:5-14. 10.3727/096368910X [DOI] [PubMed] [Google Scholar]

[szag029-B2] 2. Hoogduijn MJ, Popp F, Verbeek R, et al. The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. Int Immunopharmacol. 2010;10:1496-1500. 10.1016/j.intimp.2010.06.019 [DOI] [PubMed] [Google Scholar]

[szag029-B3] 3. Chang C, Yan J, Yao Z, et al. Effects of mesenchymal stem cell-derived paracrine signals and their delivery strategies. Adv Healthc Mater. 2021;10:e2001689. 10.1002/adhm.202001689 [DOI] [PMC free article] [PubMed] [Google Scholar]

[szag029-B4] 4. Tan Y, Salkhordeh M, Wang JP, et al. Thawed mesenchymal stem cell product shows comparable immunomodulatory potency to cultured cells In vitro and in polymicrobial septic animals. Sci Rep. 2019;9:18078. 10.1038/s41598-019-54462-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[szag029-B5] 5. Wang Y, Yi H, Song Y. The safety of MSC therapy over the past 15 years: a meta-analysis. Stem Cell Res Ther. 2021;12:545-515. 10.1186/s13287-021-02609-x [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Safety of intravascular administration of umbilical-cord-derived mesenchymal stromal cells: an updated systematic review and meta-analysis

Christine Hum

Jessica Poliwoda

Manoj Lalu

Duncan J Stewart

Shirley H J Mei

Keith R Walley

John Marshall

Asher A Mendelson

Dean A Fergusson

Shane English

Brent W Winston

John Granton

Claudia C dos Santos

Josee Champagne

Lauralyn McIntyre

Roles

Abstract

Background

Objective

Methods

Results

Conclusions

Graphical Abstract

Graphical Abstract.

Significance statement.

Introduction

Methods

Search strategy and eligibility criteria

Data analysis

Risk of bias

Results

Table 1.

Figure 1.

Risk of bias assessment

Table 2.

Safety

Figure 2.

Table 3.

Table 4.

Discussion

Conclusion

Supplementary Material

Acknowledgments

Contributor Information

Author contributions

Supplementary material

Funding

Conflicts of interest

Data availability

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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