Mesenchymal stem cells modulate pancreatic and splenic inflammation through PI3K/AKT/mTOR and TGF-β signalling in diabetic rats

Abstract

Bone marrow-derived mesenchymal stem cells (MSC) can attenuate diabetic organ damage through immunomodulatory and paracrine mechanisms, yet the specific signalling pathways engaged in the pancreas and spleen remain poorly characterized. This study investigated the effects of a single dose of undifferentiated MSC on PI3K/AKT/mTOR and TGF-β signalling, apoptotic gene expression, and tissue architecture in the pancreas and spleen of streptozotocin (STZ)-induced diabetic rats. Female rats were divided into four groups: control, diabetic (induced by streptozotocin), insulin-treated diabetic, and MSC-treated diabetic. Gene expression levels of SRY, C-Jun, P53, BCL2, P38, and Caspase3 were assessed using quantitative PCR and normalized against GAPDH. Tissue histopathology of the spleen and pancreas using H&E and immunohistochemistry (IHC) staining for PI3K, AKT, mTOR, and TGF-β were investigated. MSC-treated group showed a significant downregulation of pro-apoptotic markers Caspase3 and P53, and stress response genes P38 with upregulated anti-apoptotic gene BCL2 compared to the untreated diabetic rats. Pancreatic and splenic PI3K and AKT protein were restored following MSC treatment. Conversely, elevated TGF-β protein expression was reduced by MSC therapy, whereas mTOR remained elevated in MSC-treated tissues while lowered toward control levels by insulin. These molecular changes were accompanied by partial restoration of islet architecture and splenic histology. To our knowledge, this is among few studies concurrently characterized PI3K/AKT/mTOR and TGF-β signaling in both pancreatic and splenic tissues from the same diabetic animal. MSC therapy demonstrates a potential therapeutic role by modulating inflammatory and cell apoptotic pathways of PI3K/AKT/mTOR and TGF-β signalling with partial preservation of pancreatic and splenic tissue. A differential mTOR response was observed, whereby insulin, but not MSC treatment, restored mTOR expression toward control levels. Our findings support MSC further investigation as a regenerative adjunct to conventional diabetes management.