Mechanical force-driven TNFαendocytosis governs stem cell homeostasis

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.

Apoptotic extracellular vesicles are metabolized regulators nurturing the skin and hair

Over 300 billion of cells die every day in the human body,producing a large number of endogenous apoptotic extracellular vesicles(apoEVs).Also,allogenic stem cell transplantation,a commonly used therapeutic approach in current clinical practice,generates exogenous apoEVs.It is well known that phagocytic cells engulf and digest apoEVs to maintain the body’s homeostasis.In this study,we show that a fraction of exogenous apoEVs is metabolized in the integumentary skin and hair follicles.Mechanistically,apoEVs activate the Wnt/β-catenin pathway to facilitate their metabolism in a wave-like pattern.The migration of apoEVs is enhanced by treadmill exercise and inhibited by tail suspension,which is associated with the mechanical force-regulated expression of DKK1 in circulation.Furthermore,we show that exogenous apoEVs promote wound healing and hair growth via activation of Wnt/β-catenin pathway in skin and hair follicle mesenchymal stem cells.This study reveals a previously unrecognized metabolic pathway of apoEVs and opens a new avenue for exploring apoEV-based therapy for skin and hair disorders.

Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserine-mediated modulation of T cell receptor signaling

Mesenchymal stem cells(MSCs)influence T cells in health,disease and therapy through messengers of intercellular communication including extracellular vesicles(EVs).Apoptosis is a mode of cell death that tends to promote immune tolerance,and a large number of apoptotic vesicles(apoVs)are generated from MSCs during apoptosis.In an effort to characterize these apoVs and explore their immunomodulatory potential,here we show that after replenishing them systemically,the apoV deficiency in Fas mutant mice and pathological lymphoproliferation were rescued,leading to the amelioration of inflammation and lupus activity.ApoVs directly interacted with CD4^(+)T cells and inhibited CD25 expression and IL-2 production in a dose-dependent manner.A broad range of Th1/2/17 subsets and cytokines including IFNγ,IL17A and IL-10 were suppressed while Foxp3^(+)cells were maintained.Mechanistically,exposed phosphatidylserine(PtdSer/PS)on apoVs mediated the interaction with T cells to disrupt proximal T cell receptor signaling transduction.Remarkably,administration of apoVs prevented Th17 differentiation and memory formation,and ameliorated inflammation and joint erosion in murine arthritis.Collectively,our findings unveil a previously unrecognized crosstalk between MSC apoVs and CD4^(+)T cells and suggest a promising therapeutic use of apoVs for autoimmune diseases.