Abstract
Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases due to their immunosuppressive capacity. Here, we show that Small MSCs primed with Hypoxia and Calcium ions (SHC-MSCs) exhibit enhanced stemness and immunomodulatory functions for treating allogeneic conflicts. Compared with naïve cultured human umbilical cord blood-derived MSCs, SHC-MSCs were resistant to passage-dependent senescence mediated via the monocyte chemoattractant protein-1 and p53/p21 cascade and secreted large amounts of pro-angiogenic and immunomodulatory factors, resulting in suppression of T-cell proliferation. SHC-MSCs showed DNA demethylation in pluripotency, germline, and imprinted genes similarly to very small embryonic-like stem cells, suggesting a potential mutual relationship. Genome-wide DNA methylome and transcriptome analyses indicated that genes related to immune modulation, cell adhesion, and the cell cycle were up-regulated in SHC-MSCs. Particularly, polo-like kinase-1 (PLK1), zinc-finger protein-143, dehydrogenase/reductase-3, and friend-of-GATA2 play a key role in the beneficial effects of SHC-MSCs. Administration of SHC-MSCs or PLK1-overexpressing MSCs significantly ameliorated symptoms of graft-versus-host disease (GVHD) in a humanized mouse model, resulting in significantly improved survival, less weight loss, and reduced histopathologic injuries in GVHD target organs compared with naïve MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical treatment of allogeneic conflicts, including GVHD.
Highlights
These authors contributed : YongHwan Kim, Hye Jin Jin, Jinbeom Heo.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users. advances in allogeneic hematopoietic stem cell (SC) transplantation have improved the overall survival of patients with certain malignant and nonmalignant diseases, graft-versus-host disease (GVHD) remains a leading cause of late morbidity and mortality even following transplantation of cells acquired from human leukocyte antigen (HLA)-matched siblings [1, 2]
Advances in allogeneic hematopoietic stem cell (SC) transplantation have improved the overall survival of patients with certain malignant and nonmalignant diseases, graft-versus-host disease (GVHD) remains a leading cause of late morbidity and mortality even following transplantation of cells acquired from human leukocyte antigen (HLA)-matched siblings [1, 2]
We previously reported that senescence of umbilical cord blood (UCB)-Mesenchymal stem cells (MSCs) is orchestrated by the chemokine monocyte chemoattractant protein-1 (MCP-1; known as C-C motif ligand-2), which is secreted as a major component of the senescenceassociated secretory phenotype and is epigenetically regulated by BMI-1 [21]
Summary
Advances in allogeneic hematopoietic stem cell (SC) transplantation have improved the overall survival of patients with certain malignant and nonmalignant diseases, graft-versus-host disease (GVHD) remains a leading cause of late morbidity and mortality even following transplantation of cells acquired from human leukocyte antigen (HLA)-matched siblings [1, 2]. Most cases of GVHD are caused by the reaction of donor T-cells with histoincompatible antigens of the recipient. The standard first-line therapy for GVHD is a high dose of steroids with or without a calcineurin inhibitor to shorten the duration of steroid use [3]. There are no standards of care or agents approved by the United States Food and Drug Administration/European Medicines Agency for the second-line treatment of steroid-refractory GVHD, and novel therapies need to be urgently developed [3]
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