Autophagy Improves the Immunosuppression of CD4+ T Cells by Mesenchymal Stem Cells Through Transforming Growth Factor-β1

Abstract

Mesenchymal stem cells (MSCs) have been extensively investigated as a promising approach to treat many autoimmune and inflammatory diseases. The stress condition would affect the therapeutic efficacy and induce autophagy of MSCs. However, whether autophagy would affect the immunosuppressive capacity of MSCs is largely unknown. The present study aimed to assess whether autophagy plays an important role in regulating the immunomodulation of MSCs and the undermechanisms. We successfully inhibited and induced autophagy of MSCs using 3-methyladenine (3-MA) and rapamycin, respectively. Our results demonstrated that rapamycin strengthened the capacity of MSCs to inhibit CD4 + T-cell proliferation, whereas 3-MA weakened the inhibitory ability of MSCs. Mechanistically, 3-MA-pretreated MSCs secreted less, whereas rapamycin-pretreated MSCs secreted more transforming growth factor-b1 (TGF-b1) compared with the control cells. Furthermore, exogenous TGF-b1 addition recovered the immunosuppressive capacity of 3-MA-pretreated MSCs, whereas exogenous anti-TGF-b1 antibody addition reduced the immunosuppressive capacity of rapamycin-pretreated MSCs. These results indicated that the autophagy level regulates the immunosuppression of CD4 + T cells by MSCs through affecting TGF-b1 secretion and provides a novel method for improving the therapeutic efficacy of MSCs by activating autophagy. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1496-1505 SIGNIFICANCEMesenchymal stem cell (MSC)-based therapy is a promising tool to treat many diseases. Autophagy occurred in MSCs during their application, especially in those exposed to stress conditions. However, whether autophagy will affect the therapeutic efficacy of MSCs is largely unknown. This study makes a significant contribution to demonstrate that autophagy could improve the immunosuppression of CD4 + T cells by mesenchymal stem cells through transforming growth factor-b1. Therefore, regulation of autophagy in MSCs would provide a promising strategy to improve the therapeutic efficacy of these cells.

Superoxide dismutase 3 protects mesenchymal stem cells through enhanced autophagy and regulation of FoxO3a trafficking

“…Autophagy is essential to maintaining the cellular stemness and differentiation of MSCs ( 16 ). Similarly, autophagy in MSCs improves their wound healing capacity ( 17 ) and immunosuppressive properties ( 18 ). In addition, autophagy can degrade aggregate-prone intracytoplasmic proteins which are responsible for various neurodegenerative diseases, and it can also protect against certain infectious diseases ( 19 ).…”

Mesenchymal stromal cells and their derivatives – putative therapeutics in the management of autoimmune pancreatitis

“…Autophagic mesenchymal stromal cells have also been proven to have therapeutic benefits. MSCs derived from human bone marrow that have undergone autophagy have been proven to regulate CD4+ T helper cells via TGF‐β1 signaling [38]. Similarly, when MSCs underwent autophagy as a result of the administration of rapamycin, their ability to suppress CD4+ T helper cell proliferation was improved [38].…”

“…MSCs derived from human bone marrow that have undergone autophagy have been proven to regulate CD4+ T helper cells via TGF‐β1 signaling [38]. Similarly, when MSCs underwent autophagy as a result of the administration of rapamycin, their ability to suppress CD4+ T helper cell proliferation was improved [38]. MSCs subjected to mitochondrial transfer also seem to be effective in mitigating the symptoms of asthma [39], chronic obstructive pulmonary disorder [40], cardiomyopathy [41], acute respiratory distress syndrome, and sepsis [42].…”

“…Recently, MSC derivative therapy has been proven effective in treating pathologies that are autoimmune in nature. Apoptotic MSCs have demonstrated immunosuppressive properties in mouse models of GVHD [38], and extracellular vesicles have improved the symptoms associated with uveitis/uveoretinitis and type I diabetes mellitus [76]. In addition, exosomes have shown success in ameliorating autoimmune conditions including multiple sclerosis [77], Sjögren's syndrome [78], graft versus host disease [59], systemic lupus erythematosus [79], and rheumatoid arthritis [80].…”

Short-Term Rapamycin Preconditioning Diminishes Therapeutic Efficacy of Human Adipose-Derived Stem Cells in a Murine Model of Multiple Sclerosis

“…The preconditioning of MSCs with Rapa results in substantial improvement of their immunoregulatory function in animal models of graft vs. host disease and cutaneous wound healing [ 23 , 24 ]. Moreover, Rapa exposure has demonstrated an effective reversal of MSC senescence [ 25 , 26 , 27 ], resiliency to apoptosis-inducing stimuli [ 28 ], and robust enrichment of immunomodulatory function [ 29 , 30 , 31 ]. Furthermore, short-term Rapa exposure caused an increase in both cyclooxygenase-2 (COX2) and prostaglandin-E2 (PGE2) in bone marrow-derived mesenchymal stem cells (BMSCs) in vitro [ 30 ].…”