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: 4.59). 08/1989; 135(1):27-32.
Source: PubMed


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(4412). DOI:10.5402/2013/582689
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    • "Indeed, targeting the whole vasculature requires systemic delivery of the cells and their homing to the diseased areas. Since the first assays in 1989 [5], [6], various cell types have been tested to recover dystrophin expression in dystrophinopathic muscle [7], [8]. However, whatever the cell type used, major limitations of cell transplantation are the poor survival [9], [10] and the poor migration [11], [12] of transplanted cells. "
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    ABSTRACT: Transplantation of muscle precursor cells is of therapeutic interest for focal skeletal muscular diseases. However, major limitations of cell transplantation are the poor survival, expansion and migration of the injected cells. The massive and early death of transplanted myoblasts is not fully understood although several mechanisms have been suggested. Various attempts have been made to improve their survival or migration. Taking into account that muscle regeneration is associated with the presence of macrophages, which are helpful in repairing the muscle by both cleansing the debris and deliver trophic cues to myoblasts in a sequential way, we attempted in the present work to improve myoblast transplantation by coinjecting macrophages. The present data showed that in the 5 days following the transplantation, macrophages efficiently improved: i) myoblast survival by limiting their massive death, ii) myoblast expansion within the tissue and iii) myoblast migration in the dystrophic muscle. This was confirmed by in vitro analyses showing that macrophages stimulated myoblast adhesion and migration. As a result, myoblast contribution to regenerating host myofibres was increased by macrophages one month after transplantation. Altogether, these data demonstrate that macrophages are beneficial during the early steps of myoblast transplantation into skeletal muscle, showing that coinjecting these stromal cells may be used as a helper to improve the efficiency of parenchymal cell engraftment.
    PLoS ONE 10/2012; 7(10):e46698. DOI:10.1371/journal.pone.0046698 · 3.23 Impact Factor
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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 · 2.64 Impact Factor
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