摘要
Mesenchymal stem cells(MSCs)closely interact with the immune system,and they are known to secrete inflammatory cytokines in response to stress stimuli.The biological function of MSC-derived inflammatory cytokines remains elusive.Here,we reveal that even under physiological conditions,MSCs produce and release a low level of tumor necrosis factor alpha(TNFα),which is unexpectedly required for preserving the self-renewal and differentiation of MSCs via autocrine/paracrine signaling.Furthermore,TNFαcritically maintains MSC function in vivo during bone homeostasis.Mechanistically,we unexpectedly discovered that physiological levels of TNFαsafeguard MSC homeostasis in a receptor-independent manner through mechanical force-driven endocytosis and that endocytosed TNFαbinds to mammalian target of rapamycin(mTOR)complex 2 and restricts mTOR signaling.Importantly,inhibition of mTOR signaling by rapamycin serves as an effective osteoanabolic therapeutic strategy to protect against TNFαdeficiency and mechanical unloading.Collectively,these findings unravel the physiological framework of the dynamic TNFαshuttlebased mTOR equilibrium that governs MSC and bone homeostasis.
基金
This work was supported by grants from the National Institute of Dental and Craniofacial Research,National Institutes of Health,Department of Health and Human Services(K99E025915 to C.C.)
a Schoenleber Pilot Research Grant(to S.S.)from the University of Pennsylvania School of Dental Medicine,the Guangdong Financial Fund for High-Caliber Hospital Construction,the Postdoctoral Innovative Talents Support Program of China(BX20190380 to B.S.)
the General Program of the China Postdoctoral Science Foundation(2019M663986 to B.S.).
