Tackling the physiological barriers for successful mesenchymal stem cell transplantation into the central nervous system

Abstract

Over the past decade a lot of research has been performed towards the therapeutic use of mesenchymal stem cells (MSCs) in neurodegenerative and neuroinflammatory diseases. MSCs have shown to be beneficial in different preclinical studies of central nervous system (CNS) disorders due to their immunomodulatory properties and their capacity to secrete various growth factors. Nevertheless, most of the transplanted cells die within the first hours after transplantation and induce a neuroinflammatory response. In order to increase the efficacy of MSC transplantation, it is thus imperative to completely characterise the mechanisms mediating neuroinflammation and cell death following MSC transplantation into the CNS. Consequently, different components of these cell death- and neuroinflammation-inducing pathways can be targeted in an attempt to improve the therapeutic potential of MSCs for CNS disorders.

Expression of Vascular Endothelial Growth Factor-C (VEGF-C) and Its Receptor (VEGFR-3) in the Glial Reaction Elicited by Human Mesenchymal Stem Cell Engraftment in the Normal Rat Brain

“…Previous studies have proposed that reactive astrocytes form scar-like barriers surrounding the grafted MSCs, which sequesters them from immune effector cells, or that astrocytes infiltrating the graft may provide cellular and structural support for graft survival (Coyne et al 2006;De Vocht et al 2013a;De Vocht et al 2013b;Praet et al 2012). Our data demonstrated the induction of VEGFR-3 protein, but not its ligand, in reactive astrocytes at the graft site.…”

“…Altogether, it is likely that the neuroinflammatory response in engrafted brain tissue is not induced by MSCs secreting VEGF-C but is rather a phenomenon secondary to cell death observed after allogeneic or xenogeneic stem cell transplantation into the CNS (De Vocht et al 2013a). Previous studies have suggested that even autologous MSC grafts as well as allo-or xenogeneic stem cell grafts in the rat brain can trigger robust microglial activation and severe astrogliosis (Camp et al 2009;Tambuyzer et al 2009;Bergwerf et al 2011;De Vocht et al 2013a;De Vocht et al 2013b). In addition, Khoo et al (2011) reported that the glial reaction after transplantation of human MSCs into the rat brain occurs in the presence of cyclosporine immunosuppression, indicating that it is not specific to the transplanted cells.…”

“…Thus, only a limited number of stem cells can be stably engrafted into the brain (Bergwerf et al 2011;De Vocht et al 2013a;De Vocht et al 2013b;Praet et al 2012;Reekmans et al 2012;Tambuyzer et al 2009). These data suggest the interaction between cellular grafts and the microenvironment of the host brain, especially the glia, is important for graft survival.…”

“…These data suggest the interaction between cellular grafts and the microenvironment of the host brain, especially the glia, is important for graft survival. Furthermore, the glial reaction induced by engrafted MSCs in brain tissue is expected to have a profound influence on graft survival (Bergwerf et al 2011;De Vocht et al 2013b).…”

Pre- and postmortem imaging of transplanted cells

“…Due to insufficient GFP expression and the complexity and cost of development of transgenic animals, vector-mediating GFP transfection in vitro is still the preferred technique for GFP labeling. [166][167][168] The generation of various colors of blue/yellow-shifted GFP variants, or the mutation-based development of red fluorescent proteins from …”