Metabolic regulation of mesenchymal stem cell in expansion and therapeutic application

Liu, Yijun; Ma, Teng

doi:10.1002/btpr.2034

Cited by 49 publications

(53 citation statements)

References 147 publications

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“…Accordingly, a linear correlation of metabolic activity and T-cell suppressive capacity of MSCs was observed. In line with the observation of low glycolytic activity in senescent MSCs [26], we could previously link diminished T-cell suppression of MSCs with senescence [14]. …”

Section: Discussionsupporting

confidence: 52%

Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid

Killer¹,

Nold²,

Henkenius³

et al. 2017

Stem Cell Res Ther

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BackgroundMesenchymal stem cells (MSCs) have entered the clinic as an Advanced Therapy Medicinal Product and are currently evaluated in a wide range of studies for tissue regeneration or in autoimmune disorders. Various efforts have been made to standardize and optimize expansion and manufacturing processes, but until now reliable potency assays for the final MSC product are lacking. Because recent findings suggest superior therapeutic efficacy of freshly administered MSCs in comparison with frozen cells, we sought to correlate the T-cell suppressive capacity of MSCs with their metabolic activity.MethodsHuman MSCs were obtained from patients’ bone fragments and were employed in coculture with peripheral blood mononuclear cells (PBMCs) in an allogeneic T-cell proliferation assay to measure immunosuppressive function. Metabolic activity of MSCs was measured in real time in terms of aerobic glycolysis quantified by the extracellular acidification rate and mitochondrial respiration quantified by the oxygen consumption rate.ResultsWe show that MSC-induced suppression of T-cell proliferation was highly dependent on individual healthy donors’ lymphocytes. Moreover, coculture with PBMCs increased the glycolytic and respiratory activity of MSCs considerably in a PBMC donor-dependent manner. The twofold to threefold enhancement of cell metabolism was accompanied by higher T-cell suppressive capacities of MSCs. The cryoprotectant dimethyl sulfoxide decreased metabolic and immunosuppressive performances of MSCs while valproic acid (VPA) increased their glycolytic, respiratory and T-cell suppressive capacity.ConclusionsFunctional fitness of MSCs can be determined by measuring metabolic activity and can be enhanced by exposure to VPA. Pretesting the increment of metabolic activity upon interaction of donor MSCs with patient T-cells provides a rational approach for an individualized potency assay prior to MSC therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0553-y) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 52%

Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid

Killer¹,

Nold²,

Henkenius³

et al. 2017

Stem Cell Res Ther

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“…One great downfall of transplanted stem cell therapeutics in tissue engineering is their inability to survive the harsh hypoxic environment of the recipient tissue [64][65][66]. Their ability to survive in an environment that is deprived of both oxygen and nutrient supply is necessary for successful tissue repair and angiogenesis [67].…”

Section: Discussionmentioning

confidence: 99%

Enhanced osteogenic potential of mesenchymal stem cells from cortical bone: a comparative analysis

et al. 2015

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Introduction: Mesenchymal stem cells (MSCs) hold great promise for regenerative therapies in the musculoskeletal system. Although MSCs from bone marrow (BM-MSCs) and adipose tissue (AD-MSCs) have been extensively characterized, there is still debate as to the ideal source of MSCs for tissue-engineering applications in bone repair. Methods: MSCs were isolated from cortical bone fragments (CBF-MSCs) obtained from patients undergoing laminectomy, selected by fluorescence-activated cell sorting analysis, and tested for their potential to undergo mesodermic differentiation. CBF-MSCs were then compared with BM-MSCs and AD-MSCs for their colony-forming unit capability and osteogenic potential in both normoxia and hypoxia. After 2 and 4 weeks in inducing media, differentiation was assessed qualitatively and quantitatively by the evaluation of alkaline phosphatase (ALP) expression and mineral deposition (Von Kossa staining). Transcriptional activity of osteoblastogenesis-associated genes (Alp, RUNX2, Spp1, and Bglap) was also analyzed. Results: The cortical fraction of the bone contains a subset of cells positive for MSC-associated markers and capable of tri-lineage differentiation. The hypoxic conditions were generally more effective in inducing osteogenesis for the three cell lines. However, at 2 and 4 weeks, greater calcium deposition and ALP expression were observed in both hypoxic and normoxic conditions in CBF-MSCs compared with AD-and BM-MSCs. These functional observations were further corroborated by gene expression analysis, which showed a significant upregulation of Bglap, Alp, and Spp1, with a 22.50 (±4.55) -, 46.56 (±7.4)-, 71.46 (±4.16)-fold increase compared with their uninduced counterparts. Conclusions: This novel population of MSCs retains a greater biosynthetic activity in vitro, which was found increased in hypoxic conditions. The present study demonstrates that quantitative differences between MSCs retrieved from bone marrow, adipose, and the cortical portion of the bone with respect to their osteogenic potential exist and suggests the cortical bone as suitable candidate to use for orthopedic tissue engineering and regenerative medicine.

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“…Our previous studies show that hMSCs are metabolically plastic and that metabolic reconfiguration occurring in response to a changing environment plays a central role in regulating hMSC phenotype and adaptation to these environmental cues . In response to inflammatory stimuli, hMSCs regulate a number of immune cells, including T cells, B cells, macrophages, dendritic cells (DC), and natural killer cells.…”

Section: Introductionmentioning

confidence: 99%

Commitment to Aerobic Glycolysis Sustains Immunosuppression of Human Mesenchymal Stem Cells

Liu

Yuan

Munoz

et al. 2018

Stem Cells Translational Medicine

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113

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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. Recent studies have shown that hMSCs are metabolically heterogeneous and actively reconfigure metabolism to support the biochemical demands of tissue repair. However, how hMSCs regulate their energy metabolism to support their immunomodulatory properties is largely unknown. This study investigates hMSC metabolic reconfiguration during immune activation and provides evidence that the hMSC metabolic state significantly influences their immunomodulatory properties. 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. 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. 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. The results demonstrate the potential of altering hMSC metabolism to enhance their immunomodulatory properties and therapeutic efficacy in various diseases. Stem Cells Translational Medicine 2019;8:93–106

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Metabolic regulation of mesenchymal stem cell in expansion and therapeutic application

Cited by 49 publications

References 147 publications

Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid

Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid

Enhanced osteogenic potential of mesenchymal stem cells from cortical bone: a comparative analysis

Commitment to Aerobic Glycolysis Sustains Immunosuppression of Human Mesenchymal Stem Cells

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