Hyperglycemia compromises the ischemia-provoked dedifferentiation of cerebral pericytes through p21–SOX2 signaling in high-fat diet-induced murine model

Aim: Diabetes-related cerebral small vessel disease (CSVD) causes neurological deficits. Patients with diabetes showed pericyte loss as a hallmark of retinopathy. Cerebral pericytes, which densely localize around brain capillaries, are quiescent stem cells regulating regeneration of brain and may have a role in CSVD development. This study investigated whether diabetes impairs ischemia-provoked dedifferentiation of pericytes. Methods: A murine high-fat diet (HFD)-induced diabetes model was used. After cerebral ischemia induction in the mice, pericytes were isolated and grown for a sphere formation assay. Results: The sphere counts from the HFD group were lower than those in the chow group. As the spheres formed, pericyte marker levels decreased and SOX2 levels increased gradually in the chow group, but not in the HFD group. Before sphere formation, pericytes from the HFD group showed high p21 levels. The use of a p21 inhibitor rescued the reduction of sphere counts in the HFD group. At cellular level, hyperglycemia-induced ROS increased the level of p21 in cerebral pericytes. The p21-SOX2 signaling was then activated after oxygen-glucose deprivation. Conclusion: HFD-induced diabetes compromises the stemness of cerebral pericytes by altering p21–SOX2 signaling. These results provide evidence supporting the role of pericytes in diabetes-related CSVD and subsequent cerebral dysfunction.