Macroautophagy has been implicated in modulating the therapeutic function of mesenchymal stromal cells(MSCs).However,the biological function of chaperone-mediated autophagy(CMA)in MSCs remains elusive.Here,we found that CMA was inhibited in MSCs in response to the proinflammatory cytokines interferon-γ(IFN-γ)and tumor necrosis factor-α(TNF-α).In addition,suppression of CMA by knocking down the CMA-related lysosomal receptor lysosomal-associated membrane protein 2(LAMP-2A)in MSCs significantly enhanced the immunosuppressive effect of MSCs on T cell proliferation,and as expected,LAMP-2A overexpression in MSCs exerted the opposite effect on T cell proliferation.This effect of CMA on the immunosuppressive function of MSCs was attributed to its negative regulation of the expression of chemokine C-X-C motif ligand 10(CXCL10),which recruits inflammatory cells,especially T cells,to MSCs,and inducible nitric oxide synthase(iNOS),which leads to the subsequent inhibition of T cell proliferation via nitric oxide(NO).Mechanistically,CMA inhibition dramatically promoted IFN-γplus TNF-α-induced activation of NF-κB and STAT1,leading to the enhanced expression of CXCL10 and iNOS in MSCs.Furthermore,we found that IFN-γplus TNF-α-induced AKT activation contributed to CMA inhibition in MSCs.More interestingly,CMA-deficient MSCs exhibited improved therapeutic efficacy in inflammatory liver injury.Taken together,our findings established CMA inhibition as a critical contributor to the immunosuppressive function of MSCs induced by inflammatory cytokines nd highlighted a previously unknown function of CMA.
Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteostasis and the accumulation of toxic proteins in neurons, is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer＇s disease, Parkinson＇s disease, and amyotrophic lateral sclerosis （ALS）. The clinical pathology of ALS is complex and many genes associated with autophagy and RNA processing are mutated in patients with the familial form. But a causal relationship between autophagic dysfunction and ALS has not been fully established. More importantly, studies on the pathological mechanism of ALS are mainly based on animal models that may not precisely recapitulate the disease itself in human beings. The development of human iPSC techniques allows us to address these issues directly in human cell models that may profoundly influence drug discovery for ALS.
Prof.He Zhiying and colleagues from the Second Military Medical University published their research findings entitled"Non-viral FoxMl gene delivery to hepatocytes enhances liver repopulation"in Cell Death and Disease(2014,5:el252).Hepatocyte transplantation has been investigated as a substitute strategy of orthotopic liver transplan-
Stroke has become one of the secondary worldwide mortal diseases that burdens the family and the society both emotionally and economically. The announcement of China＇s Ministry of Health in 2008 showed that stroke had been the first cause of death in urban and rural residents.1.2 Traditional therapies such as thrombolysis, anti-platelets, and rehabilitation showed limited effects. Replacement therapy with stem cells promises to be a good solution due to its possible thorough therapy for the damaged brain area, reconstruction of neuronal circuitry, and probable long-term efficacy. Previous studies demonstrated that stem ceils have played crucial roles in various kinds of tissue repair and immune disorders such as cardiovascular diseases, skeletal diseases, arthritis diseases, and lupus erythematodes.37 Evidence from lab experiments and clinical trials implies that adipose-derived stem cells （ADSCs） would be a feasible and ideal cell therapy source because of their multi-differentiation potentials, easy collection, low invasion to donor patients, rapid in vitro amplification, reliable biosafety, non-immunogenicity, privileged immune modulation, and escaping from ethical issues.8-12： Data on neurological disease treatment found that ADSCs transplantation protected against acute inflammatory injury, delayed neuron degeneration, and improved neurological behaviors.12-15 Previously, the detailed mechanisms by which transplanted ADSCs induce functional recovery for stroke treatment are far from being clearly demonstrated. Some proposed reasonable mechanisms just stayed at the level of explanation and hypothesis due to the absence of solid experimental evidence.13-14 In this article, we analyzed the previous data to figure out some new paths or ideas which may do favor to future translational clinical studies.
