Evaluation of the Translational Readiness of Pluripotent Stem Cell–Derived Vascular Cell Therapy for Limb Ischemia: A Systematic Review and Meta-analysis
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Background
For the first time, pluripotent stem cell (PSC)-derived endothelial cells were administered to a human for peripheral artery disease (PAD), in August 2026. This translation is based on a large preclinical literature claiming that donor cells build blood vessels in animal models of limb ischemia, but whether it supports that claim has not been assessed systematically.
Methods
In this systematic review and meta-analysis, we searched MEDLINE, Web of Science, Europe PMC, and Embase to August 2026 for studies of PSC-derived vascular cells in animal models of limb ischemia with an acellular control. Limb perfusion at each experiment’s primary timepoint was pooled as Hedges’ g in a three-level random-effects model with cluster-robust variance. Donor-cell fate and a seven-level ordinal of vascular contribution were graded for every study. This meta-analysis was registered on PROSPERO (CRD420261465308).
Results
Sixty-eight studies in 69 reports met the criteria; 51 contributed 114 comparisons at primary timepoints. Cell therapy increased perfusion (Hedges’ g 2.26, 95% CI 1.72–2.79; P=4.1×10-11; I2=87.5%; 95% prediction interval −1.47 to 5.98). No prespecified moderator survived Holm–Bonferroni adjustment, including the donor-cell fate grade (P=0.30). A donor cell was resolved in a vessel wall in 35 studies, and flow through such a vessel in 7. Small-study effects were strong (Egger t=6.25, P=9×10-8) but were not reproduced by a sample-size–based test (P=0.80); trim-and-fill moved the estimate to 1.15. On the natural scale, treated limbs recovered about twice the control perfusion (ratio of means 1.96, 95% CI 1.66– 2.33). Limb preservation favored cell therapy in 11 studies with countable events (risk ratio 4.88, 95% CI 2.28–10.45), but 43 of 68 studies reported no functional outcome, and only 22 comparisons from 8 studies were both randomized and blindly assessed. In a post hoc analysis that did not survive multiplicity adjustment, effects were largest in studies whose images could not resolve their incorporation claims (g 3.23) versus those that resolved incorporation (g 2.33).
Conclusions
PSC-derived vascular cell therapy improved limb perfusion in animal models, consistently across every sensitivity analysis, although the magnitude is uncertain given heterogeneity and small-study effects. Benefit was not associated with the degree of donor-cell incorporation across studies and was largest where incorporation was least resolvable, a pattern more consistent with reporting and measurement bias than with a true mechanistic effect. The first rigorous, blinded test of that benefit may come not from animals but from the patients now receiving these cells.
Clinical Perspective
What Is New?
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This is the first meta-analysis of preclinical pluripotent stem cell (PSC)-derived vascular cell therapy for limb ischemia, completed as the first patients begin receiving these cells.
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Across 68 studies, PSC-derived vascular cells consistently improved limb perfusion (Hedges’ g 2.26), but the true magnitude is uncertain because the apparent small-study effect is partly a measurement artifact.
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The magnitude of benefit was not associated with the degree of donor-cell incorporation across studies (P=0.30) and was largest where structural incorporation was least resolvable, a pattern more consistent with reporting and measurement bias than with a true vascular-building mechanism.
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Donor cells were resolved within a vessel wall in 35 of 68 studies but blood flow through such a vessel in only 7, so engraftment is often shown while participation in a perfused conduit rarely is.
What Are the Clinical Implications?
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Clinical translation has already begun, so effect sizes taken from this literature should not be used to power a trial, because neither the pooled estimate nor its trim-and-fill adjustment provides a reliable planning value.
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Because benefit did not depend on structural incorporation, potency assays and release criteria can be based on functional perfusion rather than on vascular incorporation alone.
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Blinded outcome assessment, demonstration of flow through donor-containing vessels in the ischemic limb, and testing in aged or comorbid animals would make future preclinical studies directly informative; yet the decisive, blinded test of benefit may now come from the patients already receiving these cells.
