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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Published in:Frontiers in immunology Vol. 12; p. 631353
Main Authors: 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
Language:English
Published: Switzerland Frontiers Media S.A 04.05.2021
Subjects:
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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Summary: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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Reviewed by: Jeff K. Davies, Queen Mary University of London, United Kingdom; Lequn Li, Huazhong University of Science and Technology, China
Edited by: Vassiliki A. Boussiotis, Beth Israel Deaconess Medical Center and Harvard Medical School, United States
This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2021.631353