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

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.