IFN-γ Priming Restores Regenerative Capacity and Immunomodulation of Diabetic Adipose-Derived Stromal Cells in STZ-Diabetic Rats

Current therapies for Type 2 Diabetes (T2D) often fall short in addressing the underlying loss of insulin-producing β-cells and the harsh metabolic environment. Adipose-derived mesenchymal stromal cells (ASCs) hold significant promise for regenerative medicine due to their multipotent differentiation and immunomodulatory properties. However, the chronic inflammation and metabolic dysregulation characteristic of the diabetic microenvironment are known to impair the intrinsic functionality and therapeutic efficacy of autologous ASCs, limiting their potential in cell-based diabetes therapies. Understanding and overcoming this impairment is crucial for developing effective ASC-based treatments.

Researchers characterized adipose-derived mesenchymal stromal cells (ASCs) from Type 2 Diabetes patients (dASCs) and healthy donors (ndASCs) for phenotypic and functional differences. Microarray profiling was used to identify differentially expressed genes (DEGs) in both basal and IFN-γ/TNF-α-primed cells. miRNA-transcription factor (TF) coregulatory networks were constructed for key DEGs. In vivo, the anti-hyperglycemic effects, islet regeneration, insulin expression, and local inflammation modulation were assessed in streptozotocin (STZ)-induced diabetic rats after transplanting dASCs, ndASCs, or IFN-γ-primed dASCs (p.dASCs). This design allowed direct comparison of native vs. primed diabetic cells in a relevant disease model.

Transcriptomic analysis revealed that DEGs in dASCs were significantly enriched in pathways related to inflammation, glycerolipid metabolism, cell adhesion, cytoskeleton remodeling, angiogenesis, and insulin or hypoxia-related responses. Notably, EGFR/ERBB2 signaling, with downstream Ras/MAPK and PI3K/AKT cascades, and endocrine resistance-related pathways were significantly overrepresented in dASCs. While inflammatory responses were broadly shared, cytokine priming further exacerbated transcriptomic signatures associated with endocrine resistance and oxidative phosphorylation defects in dASCs. Key DEGs such as EGFR, ERBB2, ESR1, FOS, IL1B, JUN, KRAS, MMP9, and RUNX2 were identified as contributors to insulin resistance-related pathways and formed a basis for mechanistic hypothesis generation. In the STZ-diabetes model, dASCs displayed limited regenerative capacity and attenuated immunomodulatory function. However, these potentials were significantly enhanced and restored by IFN-γ priming, demonstrating improved anti-hyperglycemic effects and islet regeneration.

IFN-γ priming successfully restored the regenerative and immunomodulatory functions of diabetic ASCs, which were otherwise impaired in the STZ-diabetes model.