Mechanistic Studies On The Homeostatic Regulation Of Oligodendrocyte Proliferation And Differentiation In The CNS Via PDGFA In A Feedback Manner

In the vertebrate central nervous system(CNS),oligodendrocytes(OLs)form myelin sheaths around axons.Myelin sheathes ensure the rapid saltatory of electrical signals and provide metabolic support for axons.Abnormal myelinogenesis leads to many diseases,including multiple sclerosis,neuromyelitis optica,diffuse sclerosis,and acute disseminated encephalomyelitis.During development,some of oligodendrocyte progenitor cells(OPCs)differentiate into oligodendrocytes,and the remaining OPCs need to proliferate to stabilize the number of OPCs.Especially in the white matter of CNS,rapidly OL production requires efficient OPC proliferation.However,it is still largely unknown about the mechanism of homeostatic regulation of OPC proliferation and differentiation.Our previous studies showed that blocking Notch signaling in OPCs stimulated their differentiation.However,we detected a rapid OPC proliferation following the premature OL differentiation.This is the first observation that premature OPC differentiation and their excessive proliferation occurred successively.These data reminded us of the homeostatic phenomenon between OPC proliferation and differentiation in the CNS,especially in the white matter.On this basis,we conducted a series of explorations around the regulation mechanism of OPC homeostasis,and came to the following conclusions:(1)Blocking Notch pathway in OPCs stimulates their differentiation,and produced a large number of PDGFA+ newly formed oligodendrocytes(NFOs),suggesting that PDGFA from NFOs may be responsible for the hyperproliferation of the remaining OPCs;(2)sc RNA-seq and in situ hybridization analysis showed that NFOs indeed highly express PDGFA in vivo during development;(3)The number of OPCs in white matter was significantly reduced in Olig1-Cre mediated Myrf-CKO mutant mice,in which OPCs cannot differentiate into NFOs;(4)Forced expression of PDGFA in the cerebral cortex led to localized hyperproliferation of OPCs,but the results also showed that PDGFA expressed by neurons could not act remotely on white matter through axonal secretion.The above results prompted us to put forward a new hypothesis,that is,when OPCs differentiate into NFOs,NFOs transiently express PDGFA,which stimulates the proliferation of surrounding OPCs,to finely regulate OPCs differentiation and proliferation homeostasis through a feedback mechanism.Finally,using Cnp-Cre mediated Pdgfa conditional knockout mice,we confirmed that PDGFA expressed in NFOs plays a critical role in maintaining the proliferative homeostasis of OPCs in the CNS,especially in white matter regions.The supply-demand homeostasis of OPC differentiation and proliferation is an important question in the study of myelin development.The novel OPC homeostasis maintenance mechanism proposed in this project enriches the theoretical basis about oligodendrocyte development and myelination,and may also provide a new insight for myelin-related diseases and myelin regeneration.