Adipose stem cell-derived exosomes as emerging neurotherapeutics in obesity induced diabetic neuropathy

Obesity is the most common chronic metabolic disorder, that exacerbates low-grade systemic inflammation and insulin resistance. Insulin resistance promoted by chronic caloric excess, results in systemic inflammation, ectopic lipid deposition and adipose hypertrophy. Type 2 diabetes mellitus (T2DM) is fuelled by persistent adiposity, and approximately half of T2DM patients develop diabetic neuropathies. Diabetic neuropathy causes severe morbidity, yet current treatments are only based on symptomatic and not able to regenerate damaged nerve. Due to these limitations, regenerative cell-free therapies, such as adipose stem cell derived-exosomes (ADSC-EXOs) has gained more attention. ADSC-EXOs have emerged as a promising platform for nerve regeneration. ADSC-EXOs carry a rich cargo of regulatory miRNAs reflective of the parent cell phenotype as well as angiogenic and neurotrophic factors. ADSC-EXOs avoid immune rejection and tumorigenicity. Additionally, engineered ADSC-EXOs loaded with therapeutic miRNAs such as neurotrophin-3 significantly improves axonal regrowth and remyelination. ADSC-EXOs enhance insulin signalling and glucose metabolism via modulating phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway and exosomal miRNAs (e.g., miR-155) that enhances neuronal insulin response. They also downregulate neuroinflammation by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells/ mitogen-activated protein kinase (NF-κB/MAPK) signalling and polarizing macrophages/microglia toward anti-inflammatory phenotypes. ADSC-EXOs restore mitochondrial function and ATP production in damaged neurons. ADSC-EXOs also encourage Schwann cells to release neurotrophic factors, divide and survive to help in nerve regeneration. Pro-regenerative environment was created through these combined effects in diabetic neuropathy that encourages axonal regeneration and the functional repair of injured neurons. ADSC-EXOs show promise as a potentially ground-breaking medicinal development, particularly for diabetic neuropathy.