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.
Highlights
Acute graft-vs.-host disease (GVHD) remains a frequent and when severe, often fatal complication of allogeneic stem cell transplantation [1, 2]
Our results revealed that CBti Mesenchymal stem cells (MSCs) express high levels of key immunomodulatory factors as indoleamine [29], programmed death-ligand 1 and 2 (PD-L1 and PD-L2), and cyclooxygenase 2 (COX2)
The immunosuppressive effect of CBti MSCs was validated using a xenograft acute GVHD model, generated by injecting human cryopreserved granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood progenitor cells (PBPCs) into sublethal irradiated Non-obese diabetic (NOD).Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice, while saline injected mice were used as controls (Figure 1H)
Summary
Acute graft-vs.-host disease (GVHD) remains a frequent and when severe, often fatal complication of allogeneic stem cell transplantation [1, 2]. Human cord blood tissue derived MSCs (CBti MSCs) have gained significant attention as an “off the shelf ” product for the treatment of numerous disorders including diabetes as well as acute respiratory distress syndrome (ARDS) [8, 9] Due to their abundant availability, easy, and painless collection, and high expansion potential, CBti is a suitable source of MSCs for clinical applications [8]. Immune priming of BM MSCs by exposure to the pro-inflammatory cytokine interferon-gamma (IFN-γ) promotes the modification of cell metabolism from mitochondrial respiration to cytoplasmbased aerobic glycolysis [16, 17] This aerobic state supports the secretion of the immunosuppressive factors kynurenine and prostaglandin E2 (PGE2), suggesting that the metabolic state of MSCs is associated with their immunomodulatory properties [17]. We hypothesized that preemptive priming of CBti MSCs could overcome the lack of efficacy in the treatment of GVHD by improving their metabolic fitness after thawing, increasing their
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