Mesenchymal stem cell repression of Th17 cells is triggered by mitochondrial transfer

Luz‐Crawford, Patricia; Hernandez, Javier; Djouad, Farida; Luque‐Campos, Noymar; Caicedo, Andrés; Carrère-Kremer, Séverine; Brondello, Jean-Marc; Vignais, Marie-Luce; Pène, Jérôme; Jørgensen, Christian

doi:10.1186/s13287-019-1307-9

Cited by 91 publications

(76 citation statements)

References 34 publications

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“…MSCs have also been reported to transfer mitochondria to immune cells including T cells and macrophages. In these settings, transferred mitochondria decreased inflammation by promoting recipient immune cell differentiation towards an anti-inflammatory phenotype [ 111 , 112 , 113 , 114 , 115 , 116 ]. On the contrary, the transfer to T cells of mitochondria originating from myeloid cells was shown to exacerbate inflammation and to lead to asthma aggravation [ 117 ].…”

Section: Mitochondria As Signaling Organelles: Functional Effectsmentioning

confidence: 99%

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Nakhle

Rodriguez

Vignais

2020

IJMS

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Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.

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Section: Mitochondria As Signaling Organelles: Functional Effectsmentioning

confidence: 99%

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Nakhle

Rodriguez

Vignais

2020

IJMS

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“…Thus, these results suggest that the immunoregulatory potential of MSC involves other metabolic pathways than those related to PPARβ/δ. Indeed, recently it has been demonstrated that mitochondrial transfer from MSC to T cells represents a novel mechanism of immunosuppression involved in the inhibition of Th17 cell proliferation and function as well as in the generation of regulatory T cells to restrain inflammation 13,14 . Thus, the improved immunosuppressive activity of MSC PPARβ/δ −/− could be associated to their higher mitochondrial transfer capacity as compared to MSC PPARβ/δ +/+ .…”

Section: Discussionmentioning

confidence: 99%

PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties

Contreras-López

Elizondo‐Vega

Torres

et al. 2020

Sci Rep

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Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARβ/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARβ/δ on MSC metabolic activity and the relevance of PPARβ/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARβ/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARβ/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARβ/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility. Recently, we have identified a novel role of PPARβ/δ in addition to its well described role in lipid catabolism and glucose homeostasis 1. Indeed, we have demonstrated that the expression level of PPARβ/δ, highly expressed by mesenchymal stem cell (MSC), predicts their immunoregulatory potential and that MSC priming based on PPARβ/δ inhibition enhances their immunoregulatory properties and therapeutic potential in an experimental model of arthritis 2. However, the role of PPARβ/δ on MSC metabolic activity and the relevance of PPARβ/δ metabolic control on MSC immunosuppressive properties have never been addressed. PPAR family members are nuclear-receptors that act as transcription factors upon ligand activation and lead to cell transcriptional programming. While PPAR isotypes are found in a large variety of tissues, their expression levels and functions differ according the tissue as revealed by the expression profile of targets. PPARβ/δ expressed at a high level in skeletal muscle is a key regulator of fatty acid oxidation and glucose uptake 3,4. Thus, in tissues demanding high level of energy, PPARβ/δ increase the expression level of genes associated with fatty acid transport and β-oxidation. In addition, the use of selective PPARβ/δ agonists in vivo has evidenced the antiinflammatory properties of PPARβ/δ 5. In macrophages, for instance, the activation of PPARβ/δ induces fatty acid metabolism while represses inflammation 6-8. In response to cytokines produced by Th2 cell types such as IL13 and IL4, macrophages polarize into alternatively activated macrophages that use oxidative metabolism to fuel

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“…Luz-Crawford et al reported that coculturing healthy donor-derived BMSCs with Th17 effector cells leads to mitochondrial transfer, which increases respiration in recipient Th17 cells and reprograms the energetic metabolism from glycolysis to OXPHOS; this change is associated with a reduced production of IL-17 and suppresses proinflammatory functions of Th17 effector cells. Interestingly, coculture with rheumatoid arthritis patient-derived BMSCs showed that mitochondrial transfer is impaired compared with that with healthy donor-derived BMSCs, suggesting that resident tissue MSCs may represent a regulatory niche to balance the proinflammatory and anti-inflammatory responses; and part of the regulatory mechanisms may be mediated by mitochondrial transfer from MSCs [ 38 ]. Similarly, a study from Court et al demonstrated that mitochondrial transfer facilitates Treg differentiation through the enhanced expression of mRNA transcripts such as FOXP3, IL2RA, CTLA4, and TGFb1, which are involved in Treg cell differentiation [ 39 ].…”

Section: Mitochondrial Transfer Impacts Cellular Metabolism and Inmentioning

confidence: 99%

Mesenchymal Stem/Stromal Cell-Mediated Mitochondrial Transfer and the Therapeutic Potential in Treatment of Neurological Diseases

Han

Zheng

Wang

et al. 2020

Stem Cells International

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Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells that can be derived from various tissues. Due to their regenerative and immunomodulatory properties, MSCs have been extensively researched and tested for treatment of different diseases/indications. One mechanism that MSCs exert functions is through the transfer of mitochondria, a key player involved in many biological processes in health and disease. Mitochondria transfer is bidirectional and has an impact on both donor and recipient cells. In this review, we discussed how MSC-mediated mitochondrial transfer may affect cellular metabolism, survival, proliferation, and differentiation; how this process influences inflammatory processes; and what is the molecular machinery that mediates mitochondrial transfer. In the end, we summarized recent advances in preclinical research and clinical trials for the treatment of stroke and spinal cord injury, through application of MSCs and/or MSC-derived mitochondria.

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Mesenchymal stem cell repression of Th17 cells is triggered by mitochondrial transfer

Cited by 91 publications

References 34 publications

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties

Mesenchymal Stem/Stromal Cell-Mediated Mitochondrial Transfer and the Therapeutic Potential in Treatment of Neurological Diseases

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