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Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD

Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy...

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Autores principales: Mendt, Mayela, Daher, May, Basar, Rafet, Shanley, Mayra, Kumar, Bijender, Wei Inng, Francesca Lim, Acharya, Sunil, Shaim, Hila, Fowlkes, Natalie, Tran, Jamie P., Gokdemir, Elif, Uprety, Nadima, Nunez-Cortes, Ana K., Ensley, Emily, Mai, Thao, Kerbauy, Lucila N., Melo-Garcia, Luciana, Lin, Paul, Shen, Yifei, Mohanty, Vakul, Lu, JunJun, Li, Sufang, Nandivada, Vandana, Wang, Jing, Banerjee, Pinaki, Reyes-Silva, Francia, Liu, Enli, Ang, Sonny, Gilbert, April, Li, Ye, Wan, Xinhai, Gu, Jun, Zhao, Ming, Baran, Natalia, Muniz-Feliciano, Luis, Wilson, Jeffrey, Kaur, Indreshpal, Gagea, Mihai, Konopleva, Marina, Marin, David, Tang, Guilin, Chen, Ken, Champlin, Richard, Rezvani, Katayoun, Shpall, Elizabeth J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130860/
https://www.ncbi.nlm.nih.gov/pubmed/34017325
http://dx.doi.org/10.3389/fimmu.2021.631353
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author Mendt, Mayela
Daher, May
Basar, Rafet
Shanley, Mayra
Kumar, Bijender
Wei Inng, Francesca Lim
Acharya, Sunil
Shaim, Hila
Fowlkes, Natalie
Tran, Jamie P.
Gokdemir, Elif
Uprety, Nadima
Nunez-Cortes, Ana K.
Ensley, Emily
Mai, Thao
Kerbauy, Lucila N.
Melo-Garcia, Luciana
Lin, Paul
Shen, Yifei
Mohanty, Vakul
Lu, JunJun
Li, Sufang
Nandivada, Vandana
Wang, Jing
Banerjee, Pinaki
Reyes-Silva, Francia
Liu, Enli
Ang, Sonny
Gilbert, April
Li, Ye
Wan, Xinhai
Gu, Jun
Zhao, Ming
Baran, Natalia
Muniz-Feliciano, Luis
Wilson, Jeffrey
Kaur, Indreshpal
Gagea, Mihai
Konopleva, Marina
Marin, David
Tang, Guilin
Chen, Ken
Champlin, Richard
Rezvani, Katayoun
Shpall, Elizabeth J.
author_facet Mendt, Mayela
Daher, May
Basar, Rafet
Shanley, Mayra
Kumar, Bijender
Wei Inng, Francesca Lim
Acharya, Sunil
Shaim, Hila
Fowlkes, Natalie
Tran, Jamie P.
Gokdemir, Elif
Uprety, Nadima
Nunez-Cortes, Ana K.
Ensley, Emily
Mai, Thao
Kerbauy, Lucila N.
Melo-Garcia, Luciana
Lin, Paul
Shen, Yifei
Mohanty, Vakul
Lu, JunJun
Li, Sufang
Nandivada, Vandana
Wang, Jing
Banerjee, Pinaki
Reyes-Silva, Francia
Liu, Enli
Ang, Sonny
Gilbert, April
Li, Ye
Wan, Xinhai
Gu, Jun
Zhao, Ming
Baran, Natalia
Muniz-Feliciano, Luis
Wilson, Jeffrey
Kaur, Indreshpal
Gagea, Mihai
Konopleva, Marina
Marin, David
Tang, Guilin
Chen, Ken
Champlin, Richard
Rezvani, Katayoun
Shpall, Elizabeth J.
author_sort Mendt, Mayela
collection PubMed
description Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy has had equivocal clinical efficacy. Therapies using MSCs require optimization taking advantage of the plasticity of these cells in response to different microenvironments. In this study, we aimed to optimize cord blood tissue derived MSCs (CBti MSCs) by priming them using a regimen of inflammatory cytokines. This approach led to their metabolic reprogramming with enhancement of their glycolytic capacity. Metabolically reprogrammed CBti MSCs displayed a boosted immunosuppressive potential, with superior immunomodulatory and homing properties, even after cryopreservation and thawing. Mechanistically, primed CBti MSCs significantly interfered with glycolytic switching and mTOR signaling in T cells, suppressing T cell proliferation and ensuing polarizing toward T regulatory cells. Based on these data, we generated a Good Manufacturing Process (GMP) Laboratory protocol for the production and cryopreservation of primed CBti MSCs for clinical use. Following thawing, these cryopreserved GMP-compliant primed CBti MSCs significantly improved outcomes in a xenogenic mouse model of GVHD. Our data support the concept that metabolic profiling of MSCs can be used as a surrogate for their suppressive potential in conjunction with conventional functional methods to support their therapeutic use in GVHD or other autoimmune disorders.
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spelling pubmed-81308602021-05-19 Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD Mendt, Mayela Daher, May Basar, Rafet Shanley, Mayra Kumar, Bijender Wei Inng, Francesca Lim Acharya, Sunil Shaim, Hila Fowlkes, Natalie Tran, Jamie P. Gokdemir, Elif Uprety, Nadima Nunez-Cortes, Ana K. Ensley, Emily Mai, Thao Kerbauy, Lucila N. Melo-Garcia, Luciana Lin, Paul Shen, Yifei Mohanty, Vakul Lu, JunJun Li, Sufang Nandivada, Vandana Wang, Jing Banerjee, Pinaki Reyes-Silva, Francia Liu, Enli Ang, Sonny Gilbert, April Li, Ye Wan, Xinhai Gu, Jun Zhao, Ming Baran, Natalia Muniz-Feliciano, Luis Wilson, Jeffrey Kaur, Indreshpal Gagea, Mihai Konopleva, Marina Marin, David Tang, Guilin Chen, Ken Champlin, Richard Rezvani, Katayoun Shpall, Elizabeth J. Front Immunol Immunology Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy has had equivocal clinical efficacy. Therapies using MSCs require optimization taking advantage of the plasticity of these cells in response to different microenvironments. In this study, we aimed to optimize cord blood tissue derived MSCs (CBti MSCs) by priming them using a regimen of inflammatory cytokines. This approach led to their metabolic reprogramming with enhancement of their glycolytic capacity. Metabolically reprogrammed CBti MSCs displayed a boosted immunosuppressive potential, with superior immunomodulatory and homing properties, even after cryopreservation and thawing. Mechanistically, primed CBti MSCs significantly interfered with glycolytic switching and mTOR signaling in T cells, suppressing T cell proliferation and ensuing polarizing toward T regulatory cells. Based on these data, we generated a Good Manufacturing Process (GMP) Laboratory protocol for the production and cryopreservation of primed CBti MSCs for clinical use. Following thawing, these cryopreserved GMP-compliant primed CBti MSCs significantly improved outcomes in a xenogenic mouse model of GVHD. Our data support the concept that metabolic profiling of MSCs can be used as a surrogate for their suppressive potential in conjunction with conventional functional methods to support their therapeutic use in GVHD or other autoimmune disorders. Frontiers Media S.A. 2021-05-04 /pmc/articles/PMC8130860/ /pubmed/34017325 http://dx.doi.org/10.3389/fimmu.2021.631353 Text en Copyright © 2021 Mendt, Daher, Basar, Shanley, Kumar, Wei Inng, Acharya, Shaim, Fowlkes, Tran, Gokdemir, Uprety, Nunez-Cortes, Ensley, Mai, Kerbauy, Melo-Garcia, Lin, Shen, Mohanty, Lu, Li, Nandivada, Wang, Banerjee, Reyes-Silva, Liu, Ang, Gilbert, Li, Wan, Gu, Zhao, Baran, Muniz-Feliciano, Wilson, Kaur, Gagea, Konopleva, Marin, Tang, Chen, Champlin, Rezvani and Shpall. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Mendt, Mayela
Daher, May
Basar, Rafet
Shanley, Mayra
Kumar, Bijender
Wei Inng, Francesca Lim
Acharya, Sunil
Shaim, Hila
Fowlkes, Natalie
Tran, Jamie P.
Gokdemir, Elif
Uprety, Nadima
Nunez-Cortes, Ana K.
Ensley, Emily
Mai, Thao
Kerbauy, Lucila N.
Melo-Garcia, Luciana
Lin, Paul
Shen, Yifei
Mohanty, Vakul
Lu, JunJun
Li, Sufang
Nandivada, Vandana
Wang, Jing
Banerjee, Pinaki
Reyes-Silva, Francia
Liu, Enli
Ang, Sonny
Gilbert, April
Li, Ye
Wan, Xinhai
Gu, Jun
Zhao, Ming
Baran, Natalia
Muniz-Feliciano, Luis
Wilson, Jeffrey
Kaur, Indreshpal
Gagea, Mihai
Konopleva, Marina
Marin, David
Tang, Guilin
Chen, Ken
Champlin, Richard
Rezvani, Katayoun
Shpall, Elizabeth J.
Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD
title Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD
title_full Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD
title_fullStr Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD
title_full_unstemmed Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD
title_short Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD
title_sort metabolic reprogramming of gmp grade cord tissue derived mesenchymal stem cells enhances their suppressive potential in gvhd
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130860/
https://www.ncbi.nlm.nih.gov/pubmed/34017325
http://dx.doi.org/10.3389/fimmu.2021.631353
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