Published Data

Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation. 

Gussoni E, Bennett RR, Muskiewicz KR, Meyerrose T, Nolta JA, Gilgoff I, Stein J, Chan, YM, Lidov HG, Bönnemann CG, von Moers A, Morris GE, den Dunnen JT, Chamberlain JS, Kunkel LM and Weinberg K.  The Journal of Clinical Investigation. 110:807-814 (2002).
PMID: 12235112 [PubMed - indexed for MEDLINE]

Abstract

Duchenne muscular dystrophy (DMD) is a severe progressive muscle wasting disorder caused by mutations in the dystrophin gene.  Studies have shown that bone marrow cells transplanted into lethally irradiated mdx mice, the mouse model of DMD, can become part of skeletal muscle myofibers.  Whether or not human marrow cells also have this ability is unknown.  Here we report the analysis of muscle biopsies from a DMD patient (DMD-BMT1) who received bone marrow transplantation at age 1 year for X-linked severe combined immune deficiency (X-SCID) and was diagnosed with DMD at age 12 years.  Analysis of muscle biopsies from DMD-BMT1 revealed the presence of donor nuclei within a small number of muscle myofibers (0.5-0.9%).  The majority of the myofibers produce a truncated, in-frame isoform of dystrophin lacking exons 44 and 45 (not wild-type).  The presence of bone marrow-derived donor nuclei in the muscle of this patient documents the ability of exogenous human bone marrow cells to fuse into skeletal muscle and persist up to 13 years after transplantation.


Published Data

Role of bone marrow cell trafficking in replenishing skeletal muscle SP and MP cell populations.

Rivier F, Alkan O, Flint AF, Muskiewicz K, Allen PD, Leboulch P, Gussoni E.   Journal of Cell Science .   117:1979-1988 (2004).

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Abstract

The multipotent nature of skeletal muscle-derived side population cells is demonstrated by their myogenic and hematopoietic potential in vivo. However, whether muscle side population cells are derived from the bone marrow is unclear. To study the long-term contribution of the hematopoietic system to muscle side population, whole bone marrow cells from Ly5.1 males or from e-GFP transgenic male mice were transplanted into lethally irradiated Ly5.2 females. Long-term cell trafficking of donor bone marrow cells to muscle side population was monitored 17 times in a 34-week study. Fluorescence-activated cell sorter analyses were used to detect Ly5.1 and GFP+ donor cells, which were confirmed by fluorescence in situ hybridization of the Y-chromosome. Analyses post-transplantation indicated that whereas cells of donor origin could be found in the muscle, bone marrow cells had contributed little to the muscle side population. Attempts to increase cell tafficking by induced muscle damage again confirmed that more than 90% of side population cells present in the muscle were derived from the host. These results demonstrate that muscle side population cells are not replenished by the bone marrow and suggest a non-hematopoietic origin for this cell population.

Other Publications

Gussoni E, Pavlath GK, Lanctot AM, Sharma KR, Miller RG, Steinman L, Blau HM. Normal dystrophin transcripts detected in DMD patients after myoblast transplantation. Nature 1992; 356:435-438.

Gussoni E, Pavlath GK, Miller RG, Panzara MA, Powell M, Blau HM, Steinman L. Specific T-cell receptor gene rearrangements at the site of muscle degeneration in Duchenne muscular dystrophy. J Immunol 1994; 153:4798-4805.

Gussoni E, Wang Y, Fraefel C, Miller RG, Blau HM, Geller AI, Kunkel LM. A method to codetect introduced genes and their products in gene therapy protocols. Nature Biotechnol 1996; 14:1012-1016.

Gussoni E, Blau HM, Kunkel LM. The fate of individual myoblasts following transplantation into muscles of DMD patients. Nature Med 1997; 3:970-977.

Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, Kunkel LM, Mulligan RC. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401: 390-394 (1999).

O’Brien K, Muskiewicz K and Gussoni E. Recent advances in and therapeutic potential of muscle-derived stem cells. Journal of Cellular Biochemistry Supplement 38:80-87 (2002).

Gussoni E, Bennett RR, Muskiewicz KR, Meyerrose T, Nolta JA, Gilgoff I, Stein J, Chan, YM, Lidov HG, Bönnemann CG, von Moers A, Morris GE, den Dunnen JT, Chamberlain JS, Kunkel LM and Weinberg K. Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation. J. Clin. Invest 110:807-814 (2002).