Release date: 2007-09-06
Stem cell transplantation for Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive inheritance characterized by progressive degeneration and necrosis of skeletal muscle. Sexual muscle disease, the cause of which is a mutation or deletion of a gene encoding dystrophin on skeletal sarcolemma. DMD has no effective treatment methods so far, and finding effective treatment methods has always been a hot topic in the field of neurology. Stem cells carry the normal genome of the human body and have the potential for myogenic differentiation, causing researchers to explore the interest of muscle and non-muscle-derived adult stem cell transplantation in the treatment of DMD. Among them, bone marrow mesenchymal stem cells are ideal tissue engineering seed cells.
In 1998, Ferrari et al. injected bone marrow cells of C57/MlacZ transgenic mice bearing the β-gal genetic marker into the immunodeficient Scid/bg mice after radiotherapy through the tibialis anterior and tail veins. Immunohistochemical staining at 2 and 6 weeks showed that the tibialis anterior muscle of the experimental mice contained a β-gal positive nuclei. This indicates that bone marrow-derived myogenic precursor cells (progenitor cells) can migrate to the lesion site under the condition of muscle regeneration in the microenvironment, and differentiate into myocytes, which are involved in the repair and regeneration process of muscle fibers.
In 1999, Gussoni et al. injected normal bone marrow cells, bone marrow hematopoietic stem cells and a muscle-derived stem cell (SP cells) from normal male C57BL mice into 9 female DMD model mice (mdX mice) after radiotherapy, 5 After week, dystrophin expression was detected in the tibialis anterior muscle fibers, but less than 1%, reaching 10% after 12 weeks; and about 10% to 30% of dystrophin-expressing myocytes were detected with Y-chromosome genetic markers. Donor cell nucleus suggests that bone marrow stem cells can be directed to diseased muscle tissue through the systemic pathway of blood circulation and differentiated into muscle cells with dystrophin expression.
In the same year, research by Bittner et al. showed that bone marrow-derived stem cells not only repair skeletal muscle damage, but also induce myocardial regeneration, which indicates a promising solution to the damage of the heart muscle and respiratory muscles, which is associated with myocardial and respiratory muscle damage. Treatment is of great significance.
In 2002, Ferrari et al. instilled bone marrow cells from normal C57BL/6J mice into mdX model mice and detected <1% dystrophin-positive rate in muscle tissue. Their research established an ideal technology platform for the treatment of DMD by bone marrow stem cell transplantation.
In 2002, Gussoni reported that a 12-year-old male DMD patient underwent allogeneic bone marrow transplantation at 1 year of age for severe X-linked immunodeficiency syndrome, and a small amount of muscle fiber (0.5% to 0.9%) was found by muscle biopsy at 12 years of age. The presence of the donor's nucleus suggests that the exogenous bone marrow transplant can be fused into the host skeletal muscle cells and can persist for at least 11 years.
Zhang Cheng et al., the First Affiliated Hospital of Sun Yat-sen University, simply isolated the bone marrow cells of normal male C57BL mice into suspended hematopoietic stem cells and adherent stromal cells, plus unseparated whole bone marrow cells. The rat tail vein was transplanted into mdx mice, and it was found that bone marrow stem cells partially settled in skeletal muscle within 24 hours after transplantation, and the specific distribution index of nucleus-labeled transplanted cells in skeletal muscle of mdx rats over time. Significantly higher than normal C57 mice, suggesting that the diseased muscle tissue and its microenvironment may have specific chemotaxis to bone marrow stem cells. In addition, muscle biopsy of animals 2 to 8 months after transplantation can detect dystrophin, and has improved immunopathology, electromyography, motor function and other indicators, and the survival time of the transplanted group is longer than that of the control group.
On the basis of animal experiments, they also performed cord blood stem cell transplantation in a DMD patient with a deletion of exon 19 of the dystrophin gene. Sixty days after surgery, the patient's peripheral blood gene analysis showed a change to the normal genotype. Muscle biopsy showed neonatal myotube formation 75 days after transplantation, and dystrophin immunohistochemistry was weakly positive. DNA analysis found that donor DNA accounted for 1% to 13%. At 126 days after transplantation, muscle biopsy dystrophin immunohistochemistry showed a significant increase in positive muscle fibers, and donor DNA increased to 2.5% to 25%. The serum creatine kinase decreased from 575 U/L to 274 U/L before transplantation, and the patient's muscle strength improved slightly, which is of great significance for DMD treatment.
Allogeneic stem cell transplantation is very risky. According to statistics, the 2-year survival rate of European unrelated human leukocyte antigen (HLA)-matched cord blood stem cells after transplantation is only 69%. The main cause of death is infection and rejection after transplantation. Solving the problem of immune rejection and increasing the ratio of stem cells to differentiate into muscle cells in vivo will be the research direction of DMD stem cell therapy. ——Midi Medical Network
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