Macrophages Improve Survival, Proliferation and Migration of Engrafted Myogenic Precursor Cells into MDX Skeletal Muscle

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.

Shared signaling systems in myeloid cell-mediated muscle regeneration

“…This strategy has shown some promise in recent pre-clinical work, again using the mdx mouse model. Here, incorporation of GFP-labeled Pax7 + cells into mdx muscles was significantly greater if the Pax7 + cells were co-injected with F4/80 + mature macrophages (Lesault et al, 2012). The co-injection of macrophages also improved dispersal of the transplanted muscle cells in the recipient muscles.…”

Induction of CCAAT/Enhancer-Binding Protein β Expression With the Phosphodiesterase Inhibitor Isobutylmethylxanthine Improves Myoblast Engraftment Into Dystrophic Muscle

“…Many approaches have been investigated to enhance myoblast survival upon transplantation, including hypoxia preconditioning; heat shock; and coinjection with small molecules (dextran sulfate), biomaterials (fibrin gel), or macrophages [46][47][48][49][50]. Interestingly, C/EBPb is a potent prosurvival factor [37,38] and is upregulated in several tumors, demonstrating its role as an important mediator of cell survival during tumorigenesis [30,38].…”

Therapeutic Potential of Adipose-Derived Stem Cells and Macrophages for Ischemic Skeletal Muscle Repair

“…Interestingly, TNF-α was also reported to play a role in MyoD modulation [38,43], further emphasizing the complexity of regenerative responses. Overall, MPs were shown to actively interact with myoblasts in vitro [47] and regenerating muscle fibers in vivo [31][32]48]. As such, ASC-educated MPs may be superior for the treatment of muscle injuries due to their ability to effectively integrate signals from environmentally conditioned ASCs.…”

“…Arginase was previously shown to protect MyoD transcription factor from degradation in the highly inflammatory setting [38,42], while TNF-α was shown to be beneficial for proliferation of myoblasts [43]. The CCR2-CCL2 axis has been long recognized as a primary axis for the recruitment of MPs into injured skeletal muscle [35,[44][45] and facilitation of their interactions with myoblasts [30][31][32][46][47][48]. IL-10 is known to be a potent immunomodulatory cytokine [49][50][51].…”