When co‐cultured with LPS‐activated WT B cells, TazKD MSCs inhibited B cell proliferation and growth rate and reduced B cell secretion of immunoglobulin M compared to controls. Inhibition of glycolysis with 2‐deoxyglucose attenuated the TazKD‐mediated increased expression of cytotoxic T‐lymphocyte‐associated protein 4 and interleukin‐10. The increased glycolysis was associated with an elevated proliferation, phosphatidylinositol‐3‐kinase expression and expression of the immunosuppressive markers indoleamine‐2,3‐dioxygenase, cytotoxic T‐lymphocyte‐associated protein 4, interleukin‐10, and cluster of differentiation 59 compared to controls. In contrast, TazKD MSCs exhibited increased reactive oxygen species generation and increased glycolysis. However, mitochondrial bioenergetics and membrane potential were unaltered. MSCs from tafazzin knockdown (TazKD) mice exhibited a reduction in mitochondrial cardiolipin compared to wild type (WT) MSCs. We examined how Taz‐deficiency in murine MSCs impact their ability to modulate the function of lipopolysaccharide (LPS)‐activated wild type (WT) B lymphocytes. Mesenchymal stem cells (MSCs) are well known for their immune‐inhibitory function. Tafazzin (Taz) deficiency in BTHS patients results in an increased risk of infections. 01.īarth Syndrome (BTHS) is a rare X‐linked genetic disorder caused by mutation in the TAFAZZIN gene. GC-MS normalized peak area for (A): Lactate, (B): Citrate, and (C): succinate in the presence and absence of IFN-γ (D): glucose and (E): lactate amount in spent medium normalized to cell number and culture duration in the presence and absence of IFN-γ (F): qRT-PCR measurement of GLUT1 and HK2 mRNA level in the presence and absence of IFN-γ (G): Mitochondrial electron transport chain complex I activity and (H): total ATP amount of hMSCs in the presence and absence of IFN-γ (I): Flow-cytometric measurement of hMSCs mitochondrial membrane potential (MMP) in the presence and absence (as control) of IFN-γ (J): Absolute-total molar percent enrichment of 13 C-glucose atoms in metabolites involved in glycolysis and TCA cycle in the presence and absence of IFN-γ (K): OCR and ECAR in culture or treatment with 1 μM oligomycin a and 1uM FCCP in the presence (blue) and absence (red) of IFN-γ and (L): hMSC energy phenotype profile in the presence and absence of IFN-γ. Stem Cells Translational Medicine 2018.Įxposure of hMSC to IFN-γ reconfigures energy metabolism toward glycolysis. The results demonstrate the potential of altering hMSC metabolism to enhance their immunomodulatory properties and therapeutic efficacy in various diseases. The results also show that activation of the Akt/mTOR signaling pathway is required for metabolic reconfiguration during immune polarization and that interruption of these metabolic changes alters the immune response in IFN-γ licensed hMSCs.
IFN-γ exposure also inhibited mitochondrial electron transport activity, and the accumulation of mitochondrial reactive oxygen species plays an important signaling role in this metabolic reconfiguration. Specifically, hMSC immune polarization by interferon-gamma (IFN-γ) treatment leads to remodeling of hMSC metabolic pathways toward glycolysis, which is required to sustain the secretion of immunosuppressive factors.
This study investigates hMSC metabolic reconfiguration during immune activation and provides evidence that the hMSC metabolic state significantly influences their immunomodulatory properties. However, how hMSCs regulate their energy metabolism to support their immunomodulatory properties is largely unknown.
Recent studies have shown that hMSCs are metabolically heterogeneous and actively reconfigure metabolism to support the biochemical demands of tissue repair.
Human mesenchymal stem cells (hMSCs) promote endogenous tissue repair in part by coordinating multiple components of the host immune system in response to environmental stimuli.
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