The progress and challenges of mesenchymal stromal cell-based therapy for diabetes and its complications

Diabetes, a metabolic disorder characterized by chronic hyperglycemia resulting from insulin deficiency or resistance, continues to pose significant global health challenges with rising morbidity and mortality rates. While current therapies provide symptomatic management, they fail to address the underlying pathophysiology or prevent disease progression. Mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic approach due to their unique triad of capabilities: multilineage differentiation potential, self-renewal capacity, and potent immunomodulatory properties. Through sophisticated paracrine mechanisms, MSCs exert multifaceted therapeutic effects including angiogenesis promotion, anti-inflammatory action, tissue regeneration, and immune system regulation, positioning them as ideal candidates for diabetes intervention. This comprehensive review provides three novel contributions to the field: (1) First systematic comparison of MSC tissue sources, including umbilical cord (UC-MSCs), bone marrow (BM-MSCs) and Wharton's jelly (WJ-MSCs), for diabetes treatment efficacy; (2) Critical analysis of recently developed MSC engineering techniques to enhance therapeutic outcomes; (3) Original synthesis of optimal delivery protocols for specific diabetic complications including diabetic wounds (DW), nephropathy (DNp), retinopathy (DR), neuropathy (DNe), and cardiomyopathy (DCM). Our analysis incorporates the most recent clinical trial data (2020–2023) not covered in previous reviews. Combined with preclinical studies and clinical trials, MSC therapy demonstrates significant safety and efficacy. However, therapeutic durability remains limited, with efficacy declining by 40–60% after 6 months in most trials. This raises significant questions about its long-term clinical impact. This limitation stems primarily from poor cell engraftment and compromised survival and function within the hostile diabetic microenvironment, which is characterized by chronic inflammation, oxidative stress, and endoplasmic reticulum stress. Emerging solutions include: (1) MSC preconditioning with hypoxia; (2) Biomaterial encapsulation; and (3) Genetic modification for targeted delivery.