ABSTRACT
The development of cell or gene therapies for diseases involving cells that are widely distributed throughout the body has been severely hampered by the inability to achieve the disseminated delivery of cells or genes to the affected tissues or organ. Here we report the results of bone marrow transplantation studies in the mdx mouse, an animal model of Duchenne's muscular dystrophy, which indicate that the intravenous injection of either normal haematopoietic stem cells or a novel population of muscle-derived stem cells into irradiated animals results in the reconstitution of the haematopoietic compartment of the transplanted recipients, the incorporation of donor-derived nuclei into muscle, and the partial restoration of dystrophin expression in the affected muscle. These results suggest that the transplantation of different stem cell populations, using the procedures of bone marrow transplantation, might provide an unanticipated avenue for treating muscular dystrophy as well as other diseases where the systemic delivery of therapeutic cells to sites throughout the body is critical. Our studies also suggest that the inherent developmental potential of stem cells isolated from diverse tissues or organs may be more similar than previously anticipated.
Subject(s)
Bone Marrow Transplantation , Dystrophin/biosynthesis , Hematopoietic Stem Cell Transplantation , Muscle, Skeletal/metabolism , Muscular Dystrophy, Animal/metabolism , Animals , Cell Differentiation , Cell Nucleus , Cell Separation , Female , Genetic Therapy , Hematopoietic Stem Cells/cytology , In Situ Hybridization, Fluorescence , Male , Mice , Mice, Inbred C57BL , Muscle, Skeletal/cytology , Muscular Dystrophy, Animal/genetics , Muscular Dystrophy, Animal/therapyABSTRACT
FLRT1, FLRT2, and FLRT3 comprise a novel gene family isolated in a screen for extracellular matrix proteins expressed in muscle. The three genes encode putative type I transmembrane proteins, each containing 10 leucine-rich repeats flanked by N-terminal and C-terminal cysteine-rich regions, a fibronectin/collagen-like domain, and an intracellular tail. FLRT1 is expressed in kidney and brain, FLRT2 is expressed in pancreas, skeletal muscle, brain, and heart, and FLRT3 is expressed in kidney, brain, pancreas, skeletal muscle, lung, liver, placenta, and heart. FLRT1 localized to 11q12-q13, FLRT2 to 14q24-q32, and FLRT3 to 20p11. When expressed in SF9 and COS-1 cells, FLRT1 and FLRT2 migrate as 90- and 85-kDa proteins, respectively, and both are glycosylated. Given the overall structure of the three proteins, a function in cell adhesion and/or receptor signaling is predicted.
