Defective autophagy of pericytes enhances radiation-induced senescence promoting radiation brain injury.

ABSTRACT

BACKGROUND: Radiation-induced brain injury (RBI) represents a major challenge for cancer patients undergoing cranial radiotherapy. However, the molecular mechanisms and therapeutic strategies of RBI remain inconclusive. With the continuous exploration of the mechanisms of RBI, an increasing number of studies have implicated cerebrovascular dysfunction as a key factor in RBI-related cognitive impairment. As pericytes are a component of the neurovascular unit, there is still a lack of understanding in current research about the specific role and function of pericytes in RBI. METHODS: We constructed a mouse model of RBI-associated cognitive dysfunction in vivo and an in vitro radiation-induced pericyte model to explore the effects of senescent pericytes on the blood-brain barrier and normal CNS cells, even glioma cells. To further clarify the effects of pericyte autophagy on senescence, molecular mechanisms were explored at the animal and cellular levels. Finally, we validated the clearance of pericyte senescence by using senolytic drug and all-trans retinoic acid to investigate the role of radiation-induced pericyte senescence. RESULTS: Our findings indicated that radiation-induced pericyte senescence plays a key role in blood-brain barrier dysfunction, leading to RBI and subsequent cognitive decline. Strikingly, pericyte senescence also contributes to the growth and invasion of glioma cells. We further demonstrate that defective autophagy in pericytes is a vital regulatory mechanism for pericyte senescence. Moreover, autophagy activated by rapamycin can reverse pericyte senescence. Notably, the elimination of senescent cells by senolytic drugs significantly mitigated radiation-induced cognitive dysfunction. DISSCUSSION Our results demonstrated that pericyte senescence may be a promising therapeutic target for RBI and glioma progression.