On the short term: optimisation of myoblast transplantation techniques by enhancing their proliferative and migratory potential.
On the long term: a) reconstruction or replacement by myoblast transplantation of damaged or missing muscle following accident, surgery and ageing and b) cure of muscle and non-muscle diseases through myoblast-mediated gene transfer.
Despite the lack of success in human trials, it is generally felt that myoblast transplant holds such great potential in terms of its therapeutic applications that its optimisation should be strongly pursued. It is widely believed that rather than being intrinsically flawed, attempts at myoblast transplantation in human subjects were done prematurely, without a sufficiently thorough knowledge of the molecular and cell biological aspects of muscle regeneration. It seems likely that the key to overcome these failures will be found in autologous transplantation of satellite cells (either genetically modified or not) and in the identification and use of novel cytokines involved in muscle regeneration. Two of the crucial issues that need to be addressed are: 1) the generation of large numbers of myogenic cells, sufficient to replace a useful amount of muscle in the body, and 2) the promotion of their survival, proliferation and dispersal upon re-introduction.
During the last year a new ligand-receptor pair (Scatter Factor / Met) that controls cell growth and motility, has been shown to be implicated in muscle development. Scatter factor (SF) also promotes re-entry of adult quiescent satellite cells into the cell cycle, and sustains their proliferation and motility during regeneration. One of the aims of this project is to perform basic molecular studies, both in vitro and in vivo (in the mouse), to better understand the precise nature of the biological effects of Scatter Factor on myogenic cells. Another aim of the project is to explore the potential use of SF in enhancing the efficiency of myoblast transplant. For this purpose, SF will be added to satellite cells before and after re-injection, either alone or in combination with reconstituted extracellular matrix. Furthermore, myogenic cells engineered in vitro (or derived from genetically modified mice) to express forms of the Met receptor enhanced in its signalling ability will also be used to repopulate muscle. It has recently emerged that low-energy laser irradiation is capable of improving satellite cell proliferation in vitro and muscle regeneration in vivo. The possible synergistic effect of laser irradiation with SF will be evaluated. The use of novel cytokines (SF), or of combinations never tried before (such as SF with extracellular matrix and laser treatment), may lead to substantial improvements in availability, delivery, survival, proliferation and dispersal of transplanted myoblasts.
Funding SchemeCSC - Cost-sharing contracts
60054 Frankfurt Am Main
W12 0NN London
69978 Tel Aviv
NE4 6BE Newcastle Upon Tyne