Cell-based therapy for diabetic peripheral neuropathy: from mechanisms to clinical translation

Diabetic peripheral neuropathy (DPN) affects approximately half of all individuals with long-standing diabetes and remains without an approved disease-modifying therapy. Cell-based strategies, including bone marrow mononuclear cells (BM-MNCs) and mesenchymal stromal cells (MSCs) from various sources, have emerged as a promising approach to address this unmet need by targeting multiple pathogenic mechanisms simultaneously. This review synthesizes recent advances in cell-based therapy for DPN, spanning cell types, mechanisms, clinical evidence, and future directions. Preclinical studies have delineated several convergent mechanisms through which MSCs exert therapeutic effects in DPN models. These include preservation of Schwann cell viability and restoration of mitochondrial homeostasis via the TRPV1-[Ca²⁺]i-AMPK signaling axis, exosome-mediated delivery of neurotrophic and immunomodulatory cargo, macrophage polarization from a pro-inflammatory M1 toward a regenerative M2 phenotype, and promotion of angiogenesis through secretion of VEGF, HGF, and bFGF. Emerging evidence further implicates pericytes, the tissue-resident mesenchymal cells of the microvasculature, as both mediators of diabetic microangiopathy and potential therapeutic targets within the neurovascular unit. Clinically, BM-MNCs and umbilical cord-derived MSCs have been the most extensively evaluated cell types. A meta-analysis of seven controlled trials involving 400 patients demonstrated significant improvements in nerve conduction velocity, vibration perception threshold, and clinical symptom scores. An 8‑year follow‑up study of combined UC‑MSC and autologous BM‑MNC co‑transplantation in type 1 diabetes reported a lower incidence of new‑onset peripheral neuropathy in the treated group (7.1%) compared with controls (46.7%), suggesting a potential preventive effect. Two ongoing randomized controlled trials - RELEASE-DPN (NCT07183761) and a parallel trial from our group (ChiCTR2300071975)-are evaluating intramuscular UC-MSC regimens in refractory DPN and are expected to provide higher-level evidence regarding efficacy and durability. Among alternative sources, dental pulp stem cells have shown encouraging preclinical results, potentially related to their neural crest origin. Key challenges include heterogeneous treatment protocols, lack of consensus potency standards, and obstacles in GMP-compliant exosome manufacturing. Future priorities include head-to-head cell source comparisons, rational exosome engineering, combination regimens with pericyte-protective agents, and rigorous long-term safety surveillance. In summary, cell-based therapy represents a rapidly maturing field with the potential to transition DPN management from symptomatic relief to disease modification. Realizing this potential will require large-scale, standardized, and mechanistically informed clinical trials that incorporate validated biomarkers and extended follow-up. RELEASE DPN: ClinicalTrials.gov, NCT07183761. Registered on 14 September 2025. Our center's trial: Chinese Clinical Trial Registry, ChiCTR2300071975. Registered on 30 May 2023.