Nurturing roles of mesenchymal stem cells in reducing deficits in rodent models of Huntington's disease

Bone marrow is the most common source of mesenchymal stem cells (MSCs). Bone marrow MSCs are well-characterized as multipotential nonhematopoietic progenitor cells that can differentiate into different cell types from the mesodermal lineage (osteocytes, adipocytes, tenocytes, and chondrocytes), but also have been shown to transdifferentiate into neuro-ectodermal cells, such as astrocytes, oligodendrocytes and neurons. As useful tools for cell therapy after brain damage, MSCs have gained considerable interest due to two important functions they provide following transplantation: immunomodulation and trophic factor secretion. In terms of immunomodulatory capacities, MSCs confer several advantages. Analyses from flow cytometry indicate that MSCs express major histocompatability complex (MHC) class I, (e.g., human leucocyte antigen, or HLA, in humans), and but not MHC class II molecules, making them hypoimmunogenic when transplanted, as well as the hematopoietic markers CD45 and CD34, confirming their mesenchymal lineage. In addition, work from our lab and in other labs has shown that MSCs express anti-inflammatory cytokines. In vitro, MSCs can suppress B-cells and both CD4+ and CD8+ T-lymphocyte proliferation that are stimulated by mitogens or specific antigens. In vivo, we have found similar immunomodulatory effects on T-lymphocytes and dendritic cells after xenotransplantation of MSCs. Results from our lab show that human MSCs are not rejected in a rat striatum at 120 days after the transplantation. The hypoimmunogenicity of MSCs lends support for promoting their therapeutic use in a variety of diseases related to autoimmunity, alloreactive immunity, and even xenoreactive immunity. In terms of neurotrophic support, MSCs have been shown to secrete BDNF, NGF, GDNF and NT3 in vitro, as well as BDNF and extracellular matrix proteins, (e.g, collagen type I and fibronectin) after transplantation into the damaged brain. In addition, we have recently shown that transplants of MSCs that were genetically-engineered to overexpress BDNF protected neurons from cell death and provided significant behavioral sparing in the YAC128 mouse model of Huntington's disease (HD), a devastating genetically-transmitted neurodegenerative disorder characterized by loss of striatal output neurons, and severe cognitive, motor, and psychiatric deficits. Collectively, our results suggest that transplants of MSCs in rodent models of HD exert their behavioral effects by protecting neurons and/or creating a favorable environment to compromised neurons, rather than replacing lost neurons. As such, our findings suggest that these nurturing roles provided by MSCs may offer a promising adjunct therapy for HD.