5.7. DESCRIPCIÓN DE LA PROPUESTA
5.7.5. Lineamiento para evaluar la propuesta
The only relevant non muscle-derived stem cell, the hematopoietic stem cell (HSC), is also the most important multipotent stem cell participating
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in skeletal muscle regeneration after the SC.4,157,158 Due to their developmental plasticity in response to injury, transplantation of HSC resulted in the formation of 3.5% GFP+ myofibers, and they also contribute to the satellite cell pool.159 This percentage indicates that other stem cells play a marginal role in skeletal muscle regeneration. However, IM- or intra-venously injected donor bone marrow cells were clearly identified within both muscle connective tissue and SC niches of the host musculature.158 Other studies also observed the incorporation of donor- derived HSC cells.160,161 Another study,159 has demonstrated that HSCs also contribute to the muscle SC pool.
In general stem cells have a high proliferative capacity, which might lead to neoplastic transformations. Although there is no direct evidence for this, we should keep in mind that systemic stem cell delivery could be potentially dangerous.2,162
In summary, many types of stem cells are currently being studied for their potential in the treatment of skeletal muscle diseases. Many different populations of stem cells might be involved in muscle regeneration and can be used in the treatment of diseased skeletal muscle. However, there is still a long way to go before skeletal muscle regeneration can be routinely induced by injecting stem cells.
3.5 Conclusion
Skeletal muscle regeneration is governed by SCs and their niche, a wide range of growth factors, and probably also by other stem cells. The role of the SC niche factors has become increasingly clear in recent years. The basis for the maintenance of SC quiescence is the attachment within their specific niche by integrin α7β1, which links to cytoskeleton with laminin in the BM, and M-cadherin that attaches the SC to the adjacent myofiber. The niche ECM contributes to satellite cell quiescence by capturing stimulatory HGF. After injury, the ECM releases HGF, and the microvasculature and inflammatory cells release additional activating growth factors such as IGF-1. HGF initiates SC proliferation, while IGF- 1 stimulates both proliferation and differentiation of SCs. TGF-β1
Regulatory factors and cell populations involved in skeletal muscle regeneration
69 negatively influences these processes, and induces the formation of scar tissue. Intra-muscular injection of HGF, IGF, or decorin, seem to improve muscle regeneration. The latter by binding and inactivating TGF-β1. Correct timing of injection is essential for improvement of muscle regeneration. Besides SCs, several populations of other stem cells in muscle might be involved in the muscle regeneration process. For therapy, SCs are unsuitable at the present, because they lack the ability to cross endothelial layers, and less than 1% of the SC-derived myoblasts survives the first days after injection. Due to the limitations of SCs, the MDSCs, mesoangioblasts, pericytes, CD133+ cells, and the non muscle- derived HSCs may prove to be more suitable for the treatment of skeletal muscle injuries and diseases. However, their contribution to the satellite cell pool and future regeneration cycles remains to be established. In particular MDSCs might be promising, because of their prolonged proliferation time in vivo. Pericytes, which are able to colonize skeletal muscle after systemic injection, may also be suitable. Future research should focus on optimizing the homing of these cells to the muscle defect after local or systemic injection. Additionally, long-term research into the treatment of DMD should be performed to investigate whether these cells are able to home to the SC niche, and to participate in future regeneration cycles. Ultimately, knowledge about the factors that regulate SC activity, and the potential of other stem cells during muscle regeneration will lead to new therapies for skeletal muscle diseases.
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