Advances in cell-based therapies for Peripheral arterial disease.

Peripheral arterial disease (PAD) affects more than 230 million individuals worldwide, with critical limb ischemia (CLI) representing its most severe and life-threatening stage. Despite advances in pharmacological management and revascularization techniques, up to 40% of patients with CLI remain unsuitable for conventional interventions, underscoring the need for alternative therapeutic strategies. Cell-based therapies have emerged as a potential regenerative approach aimed at restoring microvascular perfusion, enhancing wound healing, and preventing limb loss. This narrative review critically examines the clinical translation of cell therapies for vascular regeneration, with a focus on CLI and diabetic foot ulcers. We compare the efficacy, safety, and translational maturity of major cell sources, including autologous bone marrow- and adipose-derived mesenchymal stromal cells, umbilical cord-derived cells, fetal progenitor cells, and induced pluripotent stem cell-based platforms. Current clinical evidence suggests heterogeneous efficacy across cell types, with overall favorable safety profiles but inconsistent functional outcomes. Increasing evidence indicates that paracrine signaling, immunomodulation, and angiogenic factor secretion play a more decisive role in therapeutic benefit than direct cellular engraftment or differentiation. Major barriers to clinical adoption include non-standardized manufacturing processes, lack of validated potency assays, fragmented regulatory landscapes across jurisdictions, and substantial economic constraints, with treatment costs often exceeding those of standard limb salvage or amputation strategies. Emerging innovations-such as biomaterial-assisted delivery systems, exosome-based therapies, tissue-specific progenitor cell matching, and precision patient stratification-offer potential solutions but remain largely unvalidated in large-scale trials. Overall, successful clinical translation of vascular cell therapies will require harmonized regulatory pathways, rigorous comparative clinical trials, integration of predictive biomarkers, and sustainable reimbursement models. Without these advances, cell-based therapies are likely to remain confined to experimental use in highly selected patient populations.