246. Gender Differences in Transplantation Efficiency Using Muscle-Derived Stem Cells for Muscular Dystrophy

Abstract

Top of pageAbstract Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle disease characterized by progressive muscle weakness due to the lack of dystrophin expression at the sarcolemma of muscle fibers. Transplantation of normal myoblasts into diseased muscle provides donor myoblasts that fuse with dystrophic muscle fibers and restore dystrophin. This process enables transient dystrophin delivery and improved strength in the injected dystrophic muscle. However, the approach has limitations, including immune rejection, poor cellular survival rates, and limited dissemination of the donor cells. The outcome of this cell transplantation therapy has been improved in the murine DMD model (mdx) by using muscle-derived stem cells (MDSCs). This enhanced success appears to be attributable to several unique features of stem cells: 1) self-renewal with production of identical progeny, 2) appearance early in development and persistence throughout life, and 3) long-term proliferation and multipotency. The purpose of this study was to explore potential gender differences on transplantation efficiency. Specifically, we sought to determine whether there is a difference in 1) the regeneration efficiency of male- versus female-derived MDSCs and 2) the receptiveness of the male and female mdx hosts to transplantation. Our studies found that a donor population of MT (male, three-weeks donor) did not have the same level of engraftment as FT (female, three-weeks) in terms of dystrophin delivery to mdx animals. Female MDSCs are more efficient than male MDSCs in facilitating dystrophin delivery and muscle regeneration in the murine muscular dystrophy model While we recognize there is large variability among engraftments, we found overall that the average regeneration index for the female populations was 516 dystrophin positive myofibers per 105 donor cells, and 135 fibers/105 cells for male populations (p<0.05). Several in vitro characteristics were explored to understand the in vivo differences. While both populations were isolated by the preplate technique and were capable of extended replicative lifetime, there were differences in proliferation rate, desmin expression and CD34 expression which may help to explain the differences in regeneration efficiency. Examination of the host receptiveness also revealed that female MDSC were able to achieve a much larger engraftments in female mdx hosts as compared to their performance in male mdx hosts. High engraftment was observed for female cells into female host (RI=556 fibers/10^5 cells), which supported previous results. However, these same cells have a lower engraftment when injected to age-matched male hosts (RI= 276 fibers/10^5 cells) (p=0.064).Our results imply that gender-related differences play a role in the transplantation efficiency of MDSCs. We are conducting an ongoing analysis in an attempt to better understand the mechanism by which female MDSCs support higher engraftment than male MDSCs. In addition, we are exploring possible immune responses that the male host may have to female donor cells.