? The development of stem cell therapy for numerous diseases is the goal of researchers working in a wide range of biomedical fields. As progress toward understanding the basic biology of stem cells continues to be made, it is important to maintain a focus on therapeutic applications of these cells by pursuing preclinical models. Members of our laboratory have identified a mouse muscle-derived stem cell population that exhibits an enhanced ability to regenerate skeletal muscle in a muscular dystrophy model. Transplantation of this cell population into the skeletal muscle of mice results in significantly more efficient regeneration (in terms of number of regenerating dystrophin positive myofibers within dystrophic muscle) than does myoblast transplantation therapy, which has been the focus of human clinical trials in both the United States and Canada. We hypothesize that the isolation and transplantation of more potent stem cells such as human muscle-derived stem cells (huMDSCs) or human cord blood stem cells will improve the outcome of cell therapy for muscular dystrophy. We propose here to use a preclinical model to test our ability both to expand human muscle-derived cell populations to achieve therapeutic cell doses (of quality stem cells) and to regenerate skeletal muscle. The primary goals of the cell therapy approach are 1) to generate clinically relevant numbers of (quality or robust) huMDSCs, 2) to maintain their stem cell phenotype, and 3) to prevent their in vitro transformation/ understand their limits. Together these things will increase the quantity of the robust stem cells by maintaining their potent phenotype.
In Specific Aim 1 of this proposal, we will expand huMDSC and cord blood stem cell populations to identify the proliferative limits, measure expansion kinetics, and predict clinical expansion time.
In Specific Aim 2, we will evaluate the expanded populations for any indication of transformation associated with in vitro aging. We will test for continued self-renewal by assaying molecular markers and multipotency. Most importantly, we will examine the cells for chromosomal aberrations, loss of cell cycle controls, and senescence. We will perform in vivo experiments to test for continued regeneration efficiency and neoplastic growth.
These aims will establish standard tests by which to assess any stem cell population in a preclinical setting and will provide basic insight into the possible link between stem cells and cancer stem cells. ? ? ?
| Chirieleison, Steven M; Feduska, Joseph M; Schugar, Rebecca C et al. (2012) Human muscle-derived cell populations isolated by differential adhesion rates: phenotype and contribution to skeletal muscle regeneration in Mdx/SCID mice. Tissue Eng Part A 18:232-41 |
| Chirieleison, Steven M; Bissell, Taylor A; Scelfo, Christopher C et al. (2011) Automated live cell imaging systems reveal dynamic cell behavior. Biotechnol Prog 27:913-24 |
| Schugar, Rebecca C; Chirieleison, Steven M; Wescoe, Kristin E et al. (2009) High harvest yield, high expansion, and phenotype stability of CD146 mesenchymal stromal cells from whole primitive human umbilical cord tissue. J Biomed Biotechnol 2009:789526 |
| Deasy, Bridget M; Feduska, Joseph M; Payne, Thomas R et al. (2009) Effect of VEGF on the regenerative capacity of muscle stem cells in dystrophic skeletal muscle. Mol Ther 17:1788-98 |
