Karpati, G. et al. Dystrophin is expressed in mdx skeletal muscle fibers after normal myoblast implantation. Am. J. Pathol. 135, 27-32

Neuromuscular Research Group, Montreal Neurological Institute, McGill University, Quebec, Canada.
American Journal Of Pathology (Impact Factor: 4.6). 08/1989; 135(1):27-32.
Source: PubMed

ABSTRACT In mdx mice, the dystrophin gene of the X chromosome is defective and, as a result, immunoreactive dystrophin is undetectable in all muscle fibers of all animals of this highly inbred strain. This study showed that implantation of suspensions of clonal cultures of normal human myoblasts into different regions of quadriceps muscles of 6-to-10-day-old mdx mice or 60-day-old mdx mice (whose muscles have been crushed 4 days before implantation) results in the appearance of scattered fiber segments containing microscopically demonstrable immunoreactive dystrophin. In the animals that received the normal myoblast implantation in the prenecrotic stage of the disease (6 to 10 days of age), the dystrophin-positive fiber segments (demonstrated at ages 35, 45, and 60 days) escaped necrosis. This was determined by the absence of the characteristic chains of central nuclei, a reliable marker of prior necrosis in mdx muscle fibers. By heavy labeling of the nuclear DNA of the transplantable human myoblasts with H3-thymidine during culturing, and by sequential performance of an immunocytochemical staining for dystrophin and autoradiography on the same sections, some dystrophin-positive fiber segments were shown to contain radiolabeled myonuclei. It was concluded that nondystrophic myoblasts fused with host muscle fibers to form mosaic muscle fibers in which the normal dystrophin gene of the implanted myoblasts was expressed. This approach may be employed for the mitigation of the deleterious consequences of a gene defect in recessively inherited human muscle diseases such as Duchenne dystrophy.

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    • "They detected dystrophin in several myofibers after followups of at least 3 weeks. Similar results were reported thereafter by other researchers [8] [9], and this has become a routine in the research of myogenic-cell transplantation. Gene complementation in myofibers of humans was unequivocally confirmed in at least 3 clinical trials of myoblast transplantation [10] [11] [12] [13] (Figure 2). "
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    ABSTRACT: Myopathies produce deficits in skeletal muscle function and, in some cases, progressive and irreversible loss of skeletal muscles. The transplantation of myogenic cells, that is, cells able to differentiate into myofibers, is an experimental strategy for the potential treatment of some of these diseases. The objectives pursued by the transplantation of these cells are essentially three: (a) the fusion with the patient’s myofibers to obtain the expression of therapeutic proteins into them, (b) the neoformation of new functional myofibers in skeletal muscles that were too degenerated by the progressive degeneration, and (c) the formation of a new pool of healthy donor-derived satellite cells. Although the repertoire of myogenic cells appears to have expanded in recent years, myoblasts are the only cells that have been demonstrated to engraft in humans. The present work aims to make a comprehensive review of the subject, from its beginnings to recent advances, including the preclinical experience in different animal models and recent clinical findings.
    10/2013; 2013. DOI:10.5402/2013/582689
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    • "Satellite cells are quiescent cells, located under the basal lamina of muscle fibres [5] [6] [7] [8] that can be activated to give a pool of progeny muscle precursor cells, or myoblasts [9] [10] [11]. Myoblasts can be expanded in tissue culture and contribute to limited muscle regeneration following direct intra-muscular transplantation [12] [13] [14] [15] [16] [17] [18]. 2. Stem cell therapy for muscular dystrophies "
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    ABSTRACT: The muscular dystrophies are inherited disorders characterised by progressive muscle wasting and weakness. Stem cell therapy is considered to be one of the most promising strategies for treating muscular dystrophies. In this review, we first examine the evidence that a stem cell could be used to treat muscular dystrophies, and then discuss the criteria that an ideal stem cell should meet. We also highlight the importance of standard operation procedures to be followed for ensuring the consistent and reproducible efficacy of a particular stem cell. While at the moment the scientific community is looking for an ideal stem cell to treat muscular dystrophies, it is clear that in order for this field to benefit from therapeutic stem cell applications, additional careful investigations are required.
    Neuromuscular Disorders 11/2010; 21(1):4-12. DOI:10.1016/j.nmd.2010.10.004 · 3.13 Impact Factor
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    • "Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene, is a progressive muscle-wasting disorder characterized by continuous degeneration of muscle fibers and an eventual loss of muscle function owing to the infiltration of connective tissue (Koenig et al., 1987). Among other therapeutic approaches, over the past two decades there has been considerable experimentation with cell-based therapy as a means to treat DMD (Law et al., 1988; Karpati et al., 1989; Partridge et al., 1989). This strategy involves transplanting cells that produce a functional copy of dystrophin into an affected individual so that the donor cells can provide gene products normally absent or non-functional in the recipient. "
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    ABSTRACT: Although the contribution of bone marrow-derived cells to regenerating skeletal muscle has been repeatedly documented, there remains considerable debate as to whether this incorporation is exclusively a result of inflammatory cell fusion to regenerating myofibers or whether certain populations of bone marrow-derived cells have the capacity to differentiate into muscle. The present study uses a dual-marker approach in which GFP(+) cells were intravenously transplanted into lethally irradiated beta-galactosidase(+) recipients to allow for simple determination of donor and host contribution to the muscle. FACS analysis of cardiotoxin-damaged muscle revealed that CD45(+) bone-marrow side-population (SP) cells, a group enriched in hematopoietic stem cells, can give rise to CD45(-)/Sca-1(+)/desmin(+) cells capable of myogenic differentiation. Moreover, after immunohistochemical examination of the muscles of both SP- and whole bone marrow-transplanted animals, we noted the presence of myofibers composed only of bone marrow-derived cells. Our findings suggest that a subpopulation of bone marrow SP cells contains precursor cells whose progeny have the potential to differentiate towards a muscle lineage and are capable of de novo myogenesis following transplantation and initiation of muscle repair via chemical damage.
    Journal of Cell Science 06/2008; 121(Pt 9):1426-34. DOI:10.1242/jcs.021675 · 5.33 Impact Factor
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