MYOBLAST-MEDIATED EXPRESSION OF COLONY-STIMULATING FACTOR-I (CSF-1) IN THE CYTOKINE-DEFICIENT OP OP MOUSE/

The osteopetrotic (op/op) mouse lacks colony stimulating factor-1 (CSF -1) due to an inactivating mutation in the CSF-1 gene. Intramuscular t ransplantation of engineered myoblasts was used to introduce CSF-1 int o the circulation of op/op mice. The CSF-1 cDNA was introduced into C2 C12 mouse myoblasts in culture using retroviral mediated gene transfer : Upon transplantation into the skeletal muscle of mutant mice, physio logical levels of the cytokine were achieved systemically and elicited a biological response: circulating monocytes were induced However; bo th circulating CSF-1 levels and the induction of monocytes were transi ent. Analysis of the site of cell transplantation revealed local chang es that may account for the transience of serum cytokine levels. Macro phage markers were induced in muscle tissue implanted with CSF-1 expre ssing myoblasts: c-fms, the CSF-1 receptor as well as the lineage-rest ricted antigen F4/80. We propose that in addition to CSF-1 clearance b y Kupffer cells of the liver; macrophages that accumulated at the site of cell transplantation bound the CSF-1 produced by the muscle cell t ransplants, precluding the sustained release of this cytokine into the systemic circulation. Our studies also revealed that damage to muscle caused during cell transplantation or by freeze injury resulted in th e accumulation of macrophages in op/op mouse muscle tissue. Indeed op/ op mice were fully capable of regenerating injured muscle suggesting t he presence of as yet unidentified CSF-1-independent factors capable o f generating macrophages that presumably participate in tissue remodel ing in this cytokine-deficient mouse.