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Myoblast-mediated expression of colony stimulating factor-1 (CSF-1) in the cytokine-deficientop/op mouse

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Somatic Cell and Molecular Genetics

Abstract

The osteopetrotic (op/op) mouse lacks colony stimulating factor-1 (CSF-1) due to an inactivating mutation in the CSF-1 gene. Intramuscular transplantation of engineered myoblasts was used to introduce CSF-1 into the circulation ofop/op mice. The CSF-1 cDNA was introduced into C2C12 mouse myoblasts in culture using retroviral mediated gene transfer. Upon transplantation into the skeletal muscle of mutant mice, physiological levels of the cytokine were achieved systemically and elicited a biological response: circulating monocytes were induced. However, both circulating CSF-1 levels and the induction of monocytes were transient. Analysis of the site of cell transplantation revealed local changes that may account for the transience of serum cytokine levels. Macrophage markers were induced in muscle tissue implanted with CSF-1 expressing myoblasts:c-fms, the CSF-1 receptor as well as the lineage-restricted antigen F4/80. We propose that in addition to CSF-1 clearance by Kupffer cells of the liver, macrophages that accumulated at the site of cell transplantation bound the CSF-1 produced by the muscle cell transplants, 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 the accumulation of macrophages inop/op mouse muscle tissue. Indeed,op/op mice were fully capable of regenerating injured muscle suggesting the presence of as yet unidentified CSF-1-independent factors capable of generating macrophages that presumably participate in tissue remodeling in this cytokine-deficient mouse.

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Author notes

  1. J. Dhawan & T. A. Rando

    Present address: Stanford University School of Medicine, Palo Alto Veterans Affairs Medical Center and the Department of Neurology, 94305, Stanford, California

  2. S. E. Elson

    Present address: Exelixis Inc., I Kendall Square, 02139, Cambridge, Massachusetts

Authors and Affiliations

  1. Dept. of Molecular Pharmacology, Stanford University School of Medicine, 94305, Stanford, California

    J. Dhawan, T. A. Rando, S. E. Elson & H. M. Blau

  2. DNAX Research Institute, 94303, Palo Alto, Califorma

    F. Lee

  3. Dept. of Developmental and Molecular Biology, Albert Einstem College of Medicme, 10461, Bronx, New York

    E. R. Stanley

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  1. J. Dhawan
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  5. E. R. Stanley
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Dhawan, J., Rando, T.A., Elson, S.E. et al. Myoblast-mediated expression of colony stimulating factor-1 (CSF-1) in the cytokine-deficientop/op mouse. Somat Cell Mol Genet 22, 363–381 (1996). https://doi.org/10.1007/BF02369893

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  • DOI: https://doi.org/10.1007/BF02369893

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