Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid
Abstract Background Mesenchymal 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 manuf...
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doaj-a4507faa12cd44dd8284316bb1d827692020-11-25T02:19:06ZengBMCStem Cell Research & Therapy1757-65122017-04-01811810.1186/s13287-017-0553-yImmunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acidMadeleine C. Killer0Philipp Nold1Katharina Henkenius2Lea Fritz3Tabea Riedlinger4Christina Barckhausen5Miriam Frech6Holger Hackstein7Andreas Neubauer8Cornelia Brendel9Zentrum für Tumor- und Immunbiologie (ZTI)Zentrum für Tumor- und Immunbiologie (ZTI)Zentrum für Tumor- und Immunbiologie (ZTI)Zentrum für Tumor- und Immunbiologie (ZTI)Biochemisches InstitutDepartment of Hematology, Oncology and Immunology, Philipps-University MarburgZentrum für Tumor- und Immunbiologie (ZTI)Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University GiessenDepartment of Hematology, Oncology and Immunology, Philipps-University MarburgDepartment of Hematology, Oncology and Immunology, Philipps-University MarburgAbstract Background Mesenchymal 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. Methods Human 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. Results We 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. Conclusions Functional 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.http://link.springer.com/article/10.1186/s13287-017-0553-yMesenchymal stem cellsImmunosuppressionT-cellCryopreservationValproic acid |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Madeleine C. Killer Philipp Nold Katharina Henkenius Lea Fritz Tabea Riedlinger Christina Barckhausen Miriam Frech Holger Hackstein Andreas Neubauer Cornelia Brendel |
spellingShingle |
Madeleine C. Killer Philipp Nold Katharina Henkenius Lea Fritz Tabea Riedlinger Christina Barckhausen Miriam Frech Holger Hackstein Andreas Neubauer Cornelia Brendel Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid Stem Cell Research & Therapy Mesenchymal stem cells Immunosuppression T-cell Cryopreservation Valproic acid |
author_facet |
Madeleine C. Killer Philipp Nold Katharina Henkenius Lea Fritz Tabea Riedlinger Christina Barckhausen Miriam Frech Holger Hackstein Andreas Neubauer Cornelia Brendel |
author_sort |
Madeleine C. Killer |
title |
Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid |
title_short |
Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid |
title_full |
Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid |
title_fullStr |
Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid |
title_full_unstemmed |
Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid |
title_sort |
immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid |
publisher |
BMC |
series |
Stem Cell Research & Therapy |
issn |
1757-6512 |
publishDate |
2017-04-01 |
description |
Abstract Background Mesenchymal 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. Methods Human 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. Results We 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. Conclusions Functional 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. |
topic |
Mesenchymal stem cells Immunosuppression T-cell Cryopreservation Valproic acid |
url |
http://link.springer.com/article/10.1186/s13287-017-0553-y |
work_keys_str_mv |
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