Frontiers in Immunology (May 2021)
Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD
- Mayela Mendt,
- May Daher,
- Rafet Basar,
- Mayra Shanley,
- Bijender Kumar,
- Francesca Lim Wei Inng,
- Sunil Acharya,
- Hila Shaim,
- Natalie Fowlkes,
- Jamie P. Tran,
- Elif Gokdemir,
- Nadima Uprety,
- Ana K. Nunez-Cortes,
- Emily Ensley,
- Thao Mai,
- Lucila N. Kerbauy,
- Lucila N. Kerbauy,
- Lucila N. Kerbauy,
- Luciana Melo-Garcia,
- Paul Lin,
- Yifei Shen,
- Vakul Mohanty,
- JunJun Lu,
- Sufang Li,
- Vandana Nandivada,
- Jing Wang,
- Pinaki Banerjee,
- Francia Reyes-Silva,
- Enli Liu,
- Sonny Ang,
- April Gilbert,
- Ye Li,
- Xinhai Wan,
- Jun Gu,
- Ming Zhao,
- Natalia Baran,
- Luis Muniz-Feliciano,
- Jeffrey Wilson,
- Indreshpal Kaur,
- Mihai Gagea,
- Marina Konopleva,
- David Marin,
- Guilin Tang,
- Ken Chen,
- Richard Champlin,
- Katayoun Rezvani,
- Elizabeth J. Shpall
Affiliations
- Mayela Mendt
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- May Daher
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Rafet Basar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Mayra Shanley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Bijender Kumar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Francesca Lim Wei Inng
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Sunil Acharya
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Hila Shaim
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Natalie Fowlkes
- Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Jamie P. Tran
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Elif Gokdemir
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Nadima Uprety
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Ana K. Nunez-Cortes
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Emily Ensley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Thao Mai
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Lucila N. Kerbauy
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Lucila N. Kerbauy
- Department of Stem Cell Transplantation and Cellular Therapy, Hospital Israelita Albert Einstein, São Paulo, Brazil
- Lucila N. Kerbauy
- Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo, São Paulo, Brazil
- Luciana Melo-Garcia
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Paul Lin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Yifei Shen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Vakul Mohanty
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- JunJun Lu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Sufang Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Vandana Nandivada
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Pinaki Banerjee
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Francia Reyes-Silva
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Enli Liu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Sonny Ang
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- April Gilbert
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Ye Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Xinhai Wan
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Jun Gu
- Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Ming Zhao
- Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Natalia Baran
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Luis Muniz-Feliciano
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Jeffrey Wilson
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Indreshpal Kaur
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Mihai Gagea
- Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- David Marin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Guilin Tang
- Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Ken Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Richard Champlin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Elizabeth J. Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- DOI
- https://doi.org/10.3389/fimmu.2021.631353
- Journal volume & issue
-
Vol. 12
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.
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