Dr. Chenran Wang is an assistant professor in the Department of Cancer Biology, University of Cincinnati College of Medicine. He is interested in autophagy, brain developmental disorders, postnatal neural stem cells (NSCs), glia, neural stem cell aging, and neurodegenerative diseases. He started his Ph.D. training to investigate the mechanisms of astrocyte reactivation after mechanical injuries in primary astrocytic culture and in stab wound animal models. He completed his postdoc in the Department of Cell and Developmental Biology, University of Michigan Medical School, where he focused his research in the functions of autophagy in brain development and neurodegeneration. He first established in vitro and in vivo systems to clarify the anti-reactive oxygen species (ROS) functions of autophagy to maintain postnatal NSCs pool and neurogenesis. Later on, using four conditional knockout mice to delete autophagy genes of Fip200, Atg16L1, Atg7, and Atg5 in adult NSCs, he revealed that the aggregation of p62/SQSTM1 in autophagy-deficient NSCs sequestered SOD1 (Superoxide Dismutase 1) in the nuclei to regulate cytosolic superoxide (a major form of cellular ROS) level. He also identified secreted chemokines of CCL5 and CXCL10 in Fip200-deficient NSCs to attract microglia into postnatal NSC niche of subventricular zone. These microglia are activated to secrete pro-inflammatory cytokines and inhibited the neurogenesis of Fip200-deficient NSCs. Dr. Wang's recent research focused on the functions of selective autophagy in NSCs under mTORC1 hyperactivation in a mouse model for tuberous sclerosis complex (TSC), which is a human neurodevelopmental disease characterized by epilepsy, autism and intellecture instability. Even mTORC1 activation was thought to suppress autophagy, Dr. Wang's research found that TSC-deficient NSCs could activate selective autophagy to degrade lipid droplets (namely lipophagy) to maintain high mTORC1 activation under energy stress conditions. This lipophagic mechanism is also applied to his studies of enhanced autophagy in the healthy aging of NSCs. Since starting his research lab in 2019, Dr. Wang worked with his lab members to develop and analyze genetic mouse models and to dissect out the cellular, molecular and metabolic mechanisms relevant to human neurodegenerative diseases and neural stem cell aging.
Mechanisms of enhanced autophagy protecting healthy aging of neural stem cells
Adult stem cells are responsible for the lifelong generation, maintenance, and repair of tissue and organ systems, and therefore are both useful models to study cellular aging and attractive candidates for causing tissue and organismal aging. Strikingly, age-related biological alterations in the brain have been associated with a progressive decline in adult neurogenesis (generation of new neurons) from neural stem cells (NSC) and correlated with functional impairments. Moreover, abnormalities in neurogenesis have been reported in neurodegenerative disorders. The role of autophagy in stem cell aging has just recently been the focus of research. Changes in autophagy level have been observed in aged stem cells (e.g. HSC), however, previous studies could not examine the consequence of increased autophagy level in stem cells during aging. The recently generated Becn1F121A/F121A knock-in mice increased autophagy, the lifespan and the healthspan. Therefore, the Becn1F121A/F121A mice provide a novel tool to investigate the functions of enhanced autophagy in stem cell aging. We analyzed the WT mice and Becn1F121A/F121A knock-in mice at different ages. Our preliminary data indicated that mutant mice protected their SVZ (subventricular zone) NSCs pool from exhaustion and promoted neurogenesis in old (>18-month) but not young (3-month) animals compared with age matched wild type mice. These results strongly suggest increased autophagy a key factor in heathy aging of NSCs and brain functions. Understanding these mechanisms will be important for the development of approaches to improve human healthspan that are based on the modulation of autophagy.