TY - JOUR
T1 - Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD
AU - Mendt, Mayela
AU - Daher, May
AU - Basar, Rafet
AU - Shanley, Mayra
AU - Kumar, Bijender
AU - Wei Inng, Francesca Lim
AU - Acharya, Sunil
AU - Shaim, Hila
AU - Fowlkes, Natalie
AU - Tran, Jamie P.
AU - Gokdemir, Elif
AU - Uprety, Nadima
AU - Nunez-Cortes, Ana K.
AU - Ensley, Emily
AU - Mai, Thao
AU - Kerbauy, Lucila N.
AU - Melo-Garcia, Luciana
AU - Lin, Paul
AU - Shen, Yifei
AU - Mohanty, Vakul
AU - Lu, Jun Jun
AU - Li, Sufang
AU - Nandivada, Vandana
AU - Wang, Jing
AU - Banerjee, Pinaki
AU - Reyes-Silva, Francia
AU - Liu, Enli
AU - Ang, Sonny
AU - Gilbert, April
AU - Li, Ye
AU - Wan, Xinhai
AU - Gu, Jun
AU - Zhao, Ming
AU - Baran, Natalia
AU - Muniz-Feliciano, Luis
AU - Wilson, Jeffrey
AU - Kaur, Indreshpal
AU - Gagea, Mihai
AU - Konopleva, Marina
AU - Marin, David
AU - Tang, Guilin
AU - Chen, Ken
AU - Champlin, Richard
AU - Rezvani, Katayoun
AU - Shpall, Elizabeth J.
N1 - Funding Information:
This work was supported in part by the generous philanthropic contributions to the University of Texas MD Anderson Cancer Center Moon Shots Program, by grants from the National Institute of Health, National Cancer Institute Program Project Applications P01 CA148600-09, R01 CA061508-24, and
Funding Information:
We thank Dr. Joanne Kurtzberg Laboratory for their help with the MSC isolation protocol. We are also thankful to all staffs and administration of The Cell Therapy Laboratory and Cord Blood Bank at MD Anderson Cancer Center for their kind support and assistance throughout the study. Funding. This work was supported in part by the generous philanthropic contributions to the University of Texas MD Anderson Cancer Center Moon Shots Program, by grants from the National Institute of Health, National Cancer Institute Program Project Applications P01 CA148600-09, R01 CA061508-24, and the Cancer Center Support (CORE) grant (CA016672) that support the Flow Cytometry and Cellular Imaging Facility and the RNA sequencing core facility at MD Anderson Cancer Center.
Publisher 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.
PY - 2021/5/4
Y1 - 2021/5/4
N2 - 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.
AB - 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.
KW - GvHD
KW - cell therapy
KW - mesenchymal stem cells
KW - metabolic reprogramming
KW - priming
KW - umbilical cord tissue
UR - http://www.scopus.com/inward/record.url?scp=85105977783&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85105977783&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.631353
DO - 10.3389/fimmu.2021.631353
M3 - Article
C2 - 34017325
AN - SCOPUS:85105977783
SN - 1664-3224
VL - 12
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 631353
ER -