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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Veröffentlicht in:	Frontiers in immunology Jg. 12; S. 631353
Hauptverfasser:	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.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Switzerland Frontiers Media S.A 04.05.2021
Schlagworte:	Animals cell therapy Cellular Reprogramming - drug effects Cellular Reprogramming - immunology Cellular Reprogramming - physiology Cellular Reprogramming Techniques - methods Cytokines - pharmacology Female Fetal Blood - cytology Graft vs Host Disease - prevention & control GvHD Hematopoietic Stem Cell Transplantation Immunology Mesenchymal Stem Cell Transplantation mesenchymal stem cells Mesenchymal Stem Cells - drug effects Mesenchymal Stem Cells - immunology Mesenchymal Stem Cells - metabolism metabolic reprogramming Mice Mice, Inbred NOD priming Quality Control umbilical cord tissue priming GvHD umbilical cord tissue cell therapy mesenchymal stem cells metabolic reprogramming
ISSN:	1664-3224, 1664-3224
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Abstract	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.
AbstractList	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.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. 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.
Author	Tran, Jamie P. Wei Inng, Francesca Lim Lu, JunJun Mendt, Mayela Shen, Yifei Shpall, Elizabeth J. Gagea, Mihai Gilbert, April Uprety, Nadima Ang, Sonny Nunez-Cortes, Ana K. Lin, Paul Li, Sufang Fowlkes, Natalie Nandivada, Vandana Ensley, Emily Gu, Jun Kaur, Indreshpal Tang, Guilin Rezvani, Katayoun Reyes-Silva, Francia Zhao, Ming Mohanty, Vakul Melo-Garcia, Luciana Konopleva, Marina Basar, Rafet Gokdemir, Elif Marin, David Liu, Enli Wang, Jing Kumar, Bijender Kerbauy, Lucila N. Wilson, Jeffrey Banerjee, Pinaki Li, Ye Champlin, Richard Daher, May Baran, Natalia Shanley, Mayra Chen, Ken Shaim, Hila Mai, Thao Wan, Xinhai Muniz-Feliciano, Luis Acharya, Sunil
AuthorAffiliation	4 Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo , São Paulo , Brazil 7 Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX , United States 3 Department of Stem Cell Transplantation and Cellular Therapy, Hospital Israelita Albert Einstein , São Paulo , Brazil 1 Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center , Houston, TX , United States 2 Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center , Houston, TX , United States 5 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center , Houston, TX , United States 6 Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center , Houston, TX , United States
AuthorAffiliation_xml	– name: 6 Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center , Houston, TX , United States – name: 5 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center , Houston, TX , United States – name: 4 Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo , São Paulo , Brazil – name: 2 Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center , Houston, TX , United States – name: 3 Department of Stem Cell Transplantation and Cellular Therapy, Hospital Israelita Albert Einstein , São Paulo , Brazil – name: 7 Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX , United States – name: 1 Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center , Houston, TX , United States
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Copyright	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. 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. 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
Copyright_xml	– notice: 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. – notice: 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. 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
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Keywords	priming GvHD umbilical cord tissue cell therapy mesenchymal stem cells metabolic reprogramming
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License	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. 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.
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Snippet	Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes...
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SubjectTerms	Animals cell therapy Cellular Reprogramming - drug effects Cellular Reprogramming - immunology Cellular Reprogramming - physiology Cellular Reprogramming Techniques - methods Cytokines - pharmacology Female Fetal Blood - cytology Graft vs Host Disease - prevention & control GvHD Hematopoietic Stem Cell Transplantation Immunology Mesenchymal Stem Cell Transplantation mesenchymal stem cells Mesenchymal Stem Cells - drug effects Mesenchymal Stem Cells - immunology Mesenchymal Stem Cells - metabolism metabolic reprogramming Mice Mice, Inbred NOD priming Quality Control umbilical cord tissue
Title	Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD
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