Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis

Dang, Song; Xu, Huanbai; Xu, Congfeng; Cai, Wei; Li, Qian; Cheng, Yih–Shyang; Jin, Min; Wang, Ruxing; Peng, Yongde; Zhang, Yi; Wu, Changping; He, Xiaozhou; Wan, Bing; Zhang, Yanyun

doi:10.4161/auto.28771

Cited by 92 publications

(115 citation statements)

References 59 publications

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“…Furthermore, let-7 could suppress components of the amino acid sensing pathway (Map4k3, RagC, and RagD) to induce autophagy, 49 which are crucial for therapeutic potential of MSC in autoimmune diseases. 50 Therefore, we could not exclude the possibility that let-7a functions through other targets. Further investigation is needed to identify the molecular network of let-7a in MSC-induced immunosuppression.…”

Section: Wwwmoleculartherapyorgmentioning

confidence: 99%

Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy

Liao

Shao

et al. 2017

Molecular Therapy

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Bone marrow-derived mesenchymal stem cells (MSCs) have been recently used in clinical treatment of inflammatory diseases. Practical strategies improving the immunosuppressive property of MSCs are urgently needed for MSC immunotherapy. In this study, we aimed to develop a microRNA-based strategy to improve MSC immunotherapy. Bioinformatic analysis revealed that let-7a targeted the 3 0 UTR of mRNA of Fas and FasL, both of which are essential for MSCs to induce T cell apoptosis. Knockdown of let-7a by specific inhibitor doubled Fas and Fas ligand (FasL) protein levels in MSCs. Because Fas attracts T cell migration and FasL induces T cell apoptosis, knockdown of let-7a significantly promoted MSC-induced T cell migration and apoptosis in vitro and in vivo. Importantly, MSCs knocked down of let-7a were more efficient to reduce the mortality, prevent the weight loss, suppress the inflammation reaction, and alleviate the tissue lesion of experimental colitis and graftversus-host disease (GVHD) mouse models. In conclusion, knockdown of let-7a significantly improved the therapeutic effect of MSC cytotherapy on inflammatory bowel diseases and GVHD. With high safety and convenience, knockdown of let-7a is a potential strategy to improve MSC therapy for inflammatory diseases in clinic.

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Section: Wwwmoleculartherapyorgmentioning

confidence: 99%

Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy

Liao

Shao

et al. 2017

Molecular Therapy

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“…Similarly, animal experiments have shown that infusion with rapamycin could promote the therapeutic efficacy of MSCs in transplantation [39,40]. Conversely, some studies have shown that inhibition of autophagy improved the immunosuppressive capacity of MSCs [41]. The different results raised a question regarding whether autophagy would improve or decrease the immunomodulation of MSCs.…”

Section: Discussionmentioning

confidence: 94%

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

Gao

Cen

Wang

et al. 2016

Stem Cells Translational Medicine

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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.

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“…The inflammatory microenvironment that can be seen in ARDS and sepsis plays important roles in regulating the proliferation, differentiation, and immunomodulatory properties of MSCs (46). However, much remains to be learned about the mechanism by which the oxidizing potential of the inflammatory microenvironment into which MSCs are given actually modulates the immunoregulatory function and fate of MSCs (46). Our study showed that autophagic proteins play a critical role in regulating MSC survival under oxidative stress.…”

Section: Original Researchmentioning

confidence: 83%

“…However, despite their impressive therapeutic potential, the poor survival and engraftment of MSCs is a major obstacle in MSC-based therapy (10). The inflammatory microenvironment that can be seen in ARDS and sepsis plays important roles in regulating the proliferation, differentiation, and immunomodulatory properties of MSCs (46). However, much remains to be learned about the mechanism by which the oxidizing potential of the inflammatory microenvironment into which MSCs are given actually modulates the immunoregulatory function and fate of MSCs (46).…”

Section: Original Researchmentioning

confidence: 99%

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Ghanta

Tsoyi

Liu

et al. 2017

Am J Respir Cell Mol Biol

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Oxidative stress resulting from inflammatory responses that occur during acute lung injury and sepsis can initiate changes in mitochondrial function. Autophagy regulates cellular processes in the setting of acute lung injury, sepsis, and oxidative stress by modulating the immune response and facilitating turnover of damaged cellular components. We have shown that mesenchymal stromal cells (MSCs) improve survival in murine models of sepsis by also regulating the immune response. However, the effect of autophagy on MSCs and MSC mitochondrial function during oxidative stress is unknown. This study investigated the effect of depletion of autophagic protein microtubule-associated protein 1 light chain 3B (LC3B) and beclin 1 (BECN1) on the response of MSCs to oxidative stress. MSCs were isolated from wild-type (WT) and LC3B 2/2 or Becn1 1/2 mice. MSCs from the LC3B 2/2 and Becn1 1/2 animals had increased susceptibility to oxidative stress-induced cell death as compared with WT MSCs. The MSCs depleted of autophagic proteins also had impaired mitochondrial function (decreased intracellular ATP, reduced mitochondrial membrane potential, and increased mitochondrial reactive oxygen species production) under oxidative stress as compared with WT MSCs. In WT MSCs, carbon monoxide (CO) preconditioning enhanced autophagy and mitophagy, and rescued the cells from oxidative stress-induced death. CO preconditioning was not able to rescue the decreased survival of MSCs from the LC3B 2/2 and Becn1 1/2 animals, further supporting the tenet that CO exerts its cytoprotective effects via the autophagy pathway.

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Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis

Cited by 92 publications

References 59 publications

Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy

Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy

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

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

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