Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response

Abstract

Mesenchymal stem cells (MSCs) have fueled ample translation for the treatment of immune-mediated diseases. They exert immunoregulatory and tissue-restoring effects. MSC-mediated transfer of mitochondria (MitoT) has been demonstrated to rescue target organs from tissue damage, yet the mechanism remains to be fully resolved. Therefore, we explored the effect of MitoT on lymphoid cells. Here, we describe dose-dependent MitoT from mitochondria-labeled MSCs mainly to CD4 + T cells, rather than CD8 + T cells or CD19 + B cells. Artificial transfer of isolated MSCderived mitochondria increases the expression of mRNA transcripts involved in T-cell activation and T regulatory cell differentiation including FOXP3, IL2RA, CTLA4, and TGFb1, leading to an increase in a highly suppressive CD25 + FoxP3 + population. In a GVHD mouse model, transplantation of MitoT-induced human T cells leads to significant improvement in survival and reduction in tissue damage and organ T CD4 + , CD8 + , and IFN-c + expressing cell infiltration. These findings point to a unique CD4 + T-cell reprogramming mechanism with pre-clinical proof-of-concept data that pave the way for the exploration of organelle-based therapies in immune diseases.

Anti-Fibrotic Effect of Human Wharton’s Jelly-Derived Mesenchymal Stem Cells on Skeletal Muscle Cells, Mediated by Secretion of MMP-1

“…It appears a pro-inflammatory environment can enhance MSC-mitochondrial transfer and MSC mitochondrial transfer to T cells can in turn educate immune cells (CD4 T cells, i.e.) [ 54 ]. In this connection, MSC paracrine functions and mitochondrial transfer capacity are interactive and linked together to promote tissue regeneration.…”

Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19

“…[5] While lodged in the lungs, the MSCs are able to release a wide variety of soluble mediators including anti-inflammatory cytokines, [6] antimicrobial peptides, [7] angiogenic growth factors, and extracellular vesicles (EVs) (Figure 1). [8] Direct cell-cell transmission of mitochondria from MSCs to respiratory epithelial and immune cells [9] has also been described. [10] A growing literature demonstrates that the pattern of anti-inflammatory mediators released is specific for the inflammatory lung environment encountered and is mediated through differential activation of damage and pathogen-associated molecular pathogen receptors expressed on MSC cell surfaces.…”

“…Human-to-human transmission occurs through respiratory droplets or contaminated surfaces. [1] The average incubation period is 5 days, but ranges from [1][2][3][4][5][6][7][8][9][10][11][12][13][14] days. Most patients present with mild respiratory tract infection, mostly commonly characterized by fever (82%) and cough (81%).…”

Human Fetal Liver MSCs are More Effective Than Adult Bone Marrow MSCs for Their Immunosuppressive, Immunomodulatory and Foxp3+ T regs Induction Capacity

“…99,100 We next checked if FL-MSCs, could also exert their immunosuppressive effect indirectly through induction of T regs, as already demonstrated for BM-MSCs. [33][34][35][36][37][38][39][40]101 When CD3/CD28 activated CD3 + CD25 − murine T cells were co-cultured in the presence of either FL or BM-MSCs we observed CD4 + CD25 + Foxp3 + and CD8 + CD25 + Foxp3 + T regs induction with both MSC types. However, very interestingly, in all conditions tested, FL-MSCs induced a higher percentage of T regs than BM-MSCs.…”

“…33 Experimental studies including ours has since been published to con rm this phenomenon and to provide mechanistic aspects. [34][35][36][37][38][39][40] Furthermore, ex vivo expanded MSCs display potent immunomodulatory effects in a wide array of animal disease models and have been validated in clinical trials to represent safe, feasible, and potentially effective immunotherapies for human immune-related disorders including graft-versus-host disease (GVHD) as well as autoimmune diseases. [41][42][43][44] A large number of these animal model studies [45][46][47][48][49][50] and clinical trials [51][52][53][54][55][56][57][58] have also documented changes in T reg number and function after systemic or localized administration of either autologous or allogeneic MSCs.…”