Bone Marrow-Derived Conventional, But Not Cloned, Mesenchymal Stem Cells Suppress Lymphocyte Proliferation and Prevent Graft-Versus-Host Disease in Rats

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs) could exert a potent immunosuppressive effect, and therefore may have a therapeutic potential in T-cell-dependent pathologies. In the present study, we aimed to determine whether MSCs could be used to control graft-versus-host disease (GvHD), a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). MSCs were isolated from Lewis rat bone morrow and then cultured in 10% FBS DMEM at 37°C for 4 weeks. The enriched conventional MSCs and macrophages were purified by auto-MACS. Cloned MSCs were obtained by cloning using the limiting dilution method and expanded up to more than 6 months. The identity of MSCs was confirmed by their typical spindle-shaped morphology and immunophenotypic criteria, based on the absence of expression of CD45 and CD11b/c molecules. Both types of MSCs were also tested for their ability to differentiate into adipocytes. We showed that MSCs, like macrophages, exhibit immunomodulatory properties capable of inhibiting T-cell proliferation stimulated by alloantigens, anti-CD3e/CD28 mAbs, and ConA in a dose-dependent manner in vitro. After performing adoptive transfer, MSCs suppressed systemic Lewis to (Lewis × DA)F1 rat GvHD. In contrast to the immunosuppressive activities of conventional MSCs, the cloned MSCs enhanced T-cell proliferation in vitro and yielded no clinical benefit in regard to the incidence or severity of GvHD. Therefore, these rat models have shown intriguing differences in the suppression effects of lymphocyte proliferation and GvHD prevention between short-term cultured conventional MSCs and cloned MSCs.

Regenerative Effects of Mesenchymal Stem Cells: Contribution of Muse Cells, a Novel Pluripotent Stem Cell Type that Resides in Mesenchymal Cells

“…MSCs are known to have pleiotropic actions; not only do they exert trophic and anti-inflammatory effects on damaged tissues by producing a variety of trophic factors and cytokines, they also modulate immunologic reactions, which is the basis for their application in graft-versus-host disease [3,4,5]. MSCs that have long been debated to have pluripotency, because they show spontaneous differentiation into mesodermal, ectodermal, or endodermal cells with a very low frequency and are known to home to the damaged site and contribute to tissue repair.…”

“…MSCs exert trophic and repair effects and have been applied therapeutically with various kinds of diseases for tissue regeneration and functional restoration [4,5]. The scientific basis for the repair effect of MSCs, however, has not been clearly elucidated.…”

“…MSCs have pleiotropic actions; not only do they exert trophic and anti-inflammatory effects on damaged tissues by producing a variety of trophic factors and cytokines, but they also modulate immunologic reactions, which is the basis for their application in graft-versus-host disease [3,4,5]. …”

Stem cell–based therapies for the newborn lung and brain: Possibilities and challenges

“…Many of these, including CD63, CD81, moesin, Alix, TSG101, and HSP70, are enriched in exosomes. The effect of exosomes in vitro has mostly been focused on their interaction with the immune system, including dendritic cell maturation, and Treg and B cell responses 111, 125, 126 . Exosomes isolated from cardiac progenitor cells in culture protect from ischemia/reperfusion (I/R) injury when injected into the myocardium 103 .…”

Current status of stem cell therapy: opportunities and limitations

“…A combination therapy with MSCs and Treg cells, for example, seems to increase the immunomodulatory activity of MSCs (Kitazawa et al, 2012;Lim et al, 2014). Using in vitro and in vivo experiments, Jang et al demonstrated that placenta-derived MSCs transplanted into mice can control GVHD after hematopoietic stem cell transplantation .…”