Type 2 Diabetes-Induced Molecular and Functional Impairment of Adipose Tissue-Derived Mesenchymal Stromal Cells (ASCs) and Interferon Gamma Priming for Enhanced Diabetic ASC-Based Therapy.

Transplantation of adipose-derived mesenchymal stromal cells (ASCs) or their insulin-producing derivatives holds promise for diabetes mellitus therapy due to their regenerative properties. However, the harsh microenvironment in type 2 diabetes (T2D) likely impairs autologous ASC efficacy. This study investigated transcriptomic alterations and therapeutic efficacy of ASCs from T2D patients (dASCs) in experimental diabetes, compared to healthy donors (ndASCs), and evaluated whether inflammatory priming could enhance dASC functionality. dASCs and ndASCs were characterized phenotypically and functionally. Differentially expressed genes (DEGs) were identified via microarray profiling of basal and IFN-γ/TNF-α-primed cells. miRNA-transcription factor (TF) coregulatory networks were constructed for key DEGs. In vivo, anti-hyperglycemic effects, islet regeneration, insulin expression, and local inflammation modulation were assessed in streptozotocin (STZ)-induced diabetic rats by transplanting dASCs, ndASCs, or IFN-γ-primed dASCs (p.dASCs). DEGs in dASCs were significantly enriched in inflammation, glycerolipid metabolism, cell adhesion, cytoskeleton remodeling, angiogenesis, and insulin or hypoxia-related responses. EGFR/ERBB2 signaling, with downstream Ras/MAPK and PI3K/AKT cascades, and endocrine resistance-related pathways were significantly overrepresented. Although inflammatory responses were broadly shared, cytokine priming further exacerbated endocrine resistance and oxidative phosphorylation defects-associated transcriptomic signatures in dASCs. Key DEGs (EGFR, ERBB2, ESR1, FOS, IL1B, JUN, KRAS, MMP9, RUNX2) were identified as contributors to insulin resistance-related pathways and were used to construct a miRNA-TF coregulatory circuit for mechanistic and therapeutic hypothesis-generation. In the STZ-diabetes model, dASCs displayed limited regenerative capacity and attenuated immunomodulatory function; however, these potentials were partially restored by p.dASCs. Favorable trends in glycemic control parameters were observed with ndASCs, and C-peptide levels were significantly higher in p.dASC-treated rats compared with those receiving non-primed dASCs. The study suggests a multifaceted dysregulated transcriptomic signature in dASCs, prominently including endocrine resistance-related pathways. The therapeutic efficacy of dASCs is partially rescued by IFN-γ priming, which supports the potential of tailored preconditioning strategies for improving autologous cell therapy in diabetes.