Selection of multipotent cells and enhanced muscle reconstruction by myogenic macrophage-secreted factors (original) (raw)
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STEM CELLS, 2013
Macrophages exert either beneficial or deleterious effects on tissue repair, depending on their activation/polarization state. They are crucial for adult skeletal muscle repair, notably by acting on myogenic precursor cells. However, these interactions have not been fully characterized. Here, we explored both in vitro and in vivo, in human, the interactions of differentially activated MPs with muscle precursor cells (MPCs) during adult myogenesis and skeletal muscle regeneration. We showed in vitro that through the differential secretion of cytokines and growth factors, proinflammatory macrophages inhibited MPC fusion while anti-inflammatory macrophages strongly promoted MPC differentiation by increasing their commitment into differentiated myocytes and the formation of mature myotubes. Furthermore, the in vivo time course of expression of myogenic and macrophage markers was studied in regenerating human healthy muscle after damage. We observed that regenerating areas containing proliferating MPCs were preferentially associated with macrophages expressing pro-inflammatory markers. In the same muscle, regenerating areas containing differentiating myogenin positive MPCs were preferentially coupled to macrophages harbouring anti-inflammatory markers. These data demonstrate for the first time in human that macrophages sequentially orchestrate adult myogenesis during regeneration of damaged skeletal muscle. These results support the emerging concept that inflammation, through macrophage activation, controls stem cell fate and coordinates tissue repair.
Macrophage Therapy Activates Endogenous Muscle Stem Cells and Accelerates Muscle Regeneration
2020
Background: The effects of macrophage therapies on muscle regeneration and stem cell activation after injury remains unclear. This study aims to know the effect of macrophage therapies on muscle l regeneration and endogenous stem cell activation towards new muscleMethods: Adult male Swiss mice were subjected to an injury in the gastrocnemius, close to the myotendinous junction, using a 2-mm biopsy tube. Animals were assigned to the following groups: 1.- Injury; 2.- Injury+ clodronate. Macrophages were depleted 24 hours after injury by clodronate injection. 3. - Injury+ clodronate+ macrophage therapy. Macrophage depleted mice were treated with an intramuscularl injection of 1 million peritoneal macrophages modified with intermittent anoxia reoxygenation. Animals were sacrificed at 4, and 15 days after the injury, (n = 8 per study time). Gene expression of proliferating cell nuclear antigen(PCNA) and Ki67 as cell proliferating markers, mannose receptor Ecotype 1(MRC1) and Interleukin1...
Stem Cell and Macrophage Roles in Skeletal Muscle Regenerative Medicine
International Journal of Molecular Sciences
In severe muscle injury, skeletal muscle tissue structure and functionality can be repaired through the involvement of several cell types, such as muscle stem cells, and innate immune responses. However, the exact mechanisms behind muscle tissue regeneration, homeostasis, and plasticity are still under investigation, and the discovery of pathways and cell types involved in muscle repair can open the way for novel therapeutic approaches, such as cell-based therapies involving stem cells and peripheral blood mononucleate cells. Indeed, peripheral cell infusions are a new therapy for muscle healing, likely because autologous peripheral blood infusion at the site of injury might enhance innate immune responses, especially those driven by macrophages. In this review, we summarize current knowledge on functions of stem cells and macrophages in skeletal muscle repairs and their roles as components of a promising cell-based therapies for muscle repair and regeneration.
Skeletal muscle regeneration involves macrophage-myoblast bonding
Cell adhesion & migration, 2017
Regeneration in adult skeletal muscle relies on the activation, proliferation, and fusion of myogenic precursor cells (MPC), mostly resident satellite cells (SC). However, the regulatory mechanism during this process is still under evaluation, with the final aim to manipulate regeneration when the intrinsic mechanism is corrupted. Furthermore, intercellular connections during skeletal muscle regeneration have not been previously thoroughly documented. Our hypothesis was that a direct and close cellular interaction between SC/MPC and invading myeloid cells is a key step to control regeneration. We tested this hypothesis during different steps of skeletal muscle regeneration: (a) the recruitment of activated SC; (b) the differentiation of MPC; (c) myotubes growth, in a mouse model of crush injury. Samples harvested (3 and 5 days) post-injury were screened by light and confocal microscopy. Ultrastructural analysis was performed by conventional transmission electron microscopy (TEM) and...
PLoS ONE, 2012
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.
Altered Macrophage Phenotype Transition Impairs Skeletal Muscle Regeneration
The American Journal of Pathology, 2014
Monocyte/macrophage polarization in skeletal muscle regeneration is ill defined. We used CD11bdiphtheria toxin receptor transgenic mice to transiently deplete monocytes/macrophages at multiple stages before and after muscle injury induced by cardiotoxin. Fat accumulation within regenerated muscle was maximal when ablation occurred at the same time as cardiotoxin-induced injury. Early ablation (day 1 after cardiotoxin) resulted in the smallest regenerated myofiber size together with increased residual necrotic myofibers and fat accumulation. However, muscle regeneration after late (day 4) ablation was similar to controls. Levels of inflammatory cells in injured muscle following early ablation and associated with impaired muscle regeneration were determined by flow cytometry. Delayed, but exaggerated, monocyte [CD11b þ (CD90/B220/CD49b/NK1.1/Ly6G) À (F4/80/I-Ab/CD11c) À Ly6C þ/À ] accumulation occurred; interestingly, Ly6C þ and Ly6C À monocytes were present concurrently in ablated animals and control mice. In addition to monocytes, proinflammatory, Ly6C þ macrophage accumulation following early ablation was delayed compared to controls. In both groups, CD11b þ F4/80 þ cells exhibited minimal expression of the M2 markers CD206 and CD301. Nevertheless, early ablation delayed and decreased the transient accumulation of CD11b þ F4/80 þ Ly6C À CD301 À macrophages; in control animals, the later tissue accumulation of these cells appeared to correspond to that of antiinflammatory macrophages, determined by cytokine production and arginase activity. In summary, impairments in muscle regeneration were associated with exaggerated monocyte recruitment and reduced Ly6C À macrophages; the switch of macrophage/monocyte subsets is critical to muscle regeneration. (Am J Pathol 2014, 184: 1167e1184; http://dx.
Dual and Beneficial Roles of Macrophages During Skeletal Muscle Regeneration
Exercise and Sport Sciences Reviews, 2009
Macrophages are necessary for skeletal muscle regeneration after injury. Muscle recruits inflammatory monocytes/macrophages that switch toward an anti-inflammatory profile upon phagocytosis of debris. In vitro, proinflammatory macrophages stimulate myoblast proliferation, whereas anti-inflammatory macrophages stimulate their differentiation. Thus, macrophages are involved in both phases of skeletal muscle regeneration: first, inflammation and cleansing of necrosis, and then myogenic differentiation and tissue repair.
Stem cell reports, 2017
In skeletal muscle, new functions for vessels have recently emerged beyond oxygen and nutrient supply, through the interactions that vascular cells establish with muscle stem cells. Here, we demonstrate in human and mouse that endothelial cells (ECs) and myogenic progenitor cells (MPCs) interacted together to couple myogenesis and angiogenesis in vitro and in vivo during skeletal muscle regeneration. Kinetics of gene expression of ECs and MPCs sorted at different time points of regeneration identified three effectors secreted by both ECs and MPCs. Apelin, Oncostatin M, and Periostin were shown to control myogenesis/angiogenesis coupling in vitro and to be required for myogenesis and vessel formation during muscle regeneration in vivo. Furthermore, restorative macrophages, which have been previously shown to support myogenesis in vivo, were shown in a 3D triculture model to stimulate myogenesis/angiogenesis coupling, notably through Oncostatin M production. Our data demonstrate that ...
Macrophage Plasticity and the Role of Inflammation in Skeletal Muscle Repair
Mediators of Inflammation, 2013
Effective repair of damaged tissues and organs requires the coordinated action of several cell types, including in�ltrating in�ammatory cells and resident cells. Recent �ndings have uncovered a central role for macrophages in the repair of skeletal muscle aer acute damage. If damage persists, as in skeletal muscle pathologies such as Duchenne muscular dystrophy (DMD), macrophage in�ltration perpetuates and leads to progressive �brosis, thus exacerbating disease severity. Here we discuss how dynamic changes in macrophage populations and activation states in the damaged muscle tissue contribute to its efficient regeneration. We describe how ordered changes in macrophage polarization, from M1 to M2 subtypes, can differently affect muscle stem cell (satellite cell) functions. Finally, we also highlight some of the new mechanisms underlying macrophage plasticity and brie�y discuss the emerging implications of lymphocytes and other in�ammatory cell types in normal versus pathological muscle repair.
Molecular Therapy, 2012
Macrophages have been shown to be essential for muscle repair by delivering trophic cues to growing skeletal muscle precursors and young fibers. Here, we investigated whether human macrophages, either proinflammatory or anti-inflammatory, coinjected with human myoblasts into regenerating muscle of Rag2 -/-γC -/immunodeficient mice, could modify in vivo the kinetics of proliferation and differentiation of the transplanted human myogenic precursors. Our results clearly show that proinflammatory macrophages improve in vivo the participation of injected myoblasts to host muscle regeneration, extending the window of proliferation, increasing migration, and delaying differentiation. Interestingly, immunostaining of transplanted proinflammatory macrophages at different time points strongly suggests that these cells are able to switch to an anti-inflammatory phenotype in vivo, which then may stimulate differentiation during muscle regeneration. Conceptually, our data provide for the first time in vivo evidence strongly suggesting that proinflammatory macrophages play a supportive role in the regulation of myoblast behavior after transplantation into preinjured muscle, and could thus potentially optimize transplantation of myogenic progenitors in the context of cell therapy.