Proinflammatory Macrophages Enhance the Regenerative Capacity of Human Myoblasts by Modifying Their Kinetics of Proliferation and Differentiation

Abstract

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.

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

“…According to our studies, early delivery of M1 mMPs promotes faster muscle repair [24]. Other reports also showed the benefit of M1 mMPs in accelerating tissue recovery post-injury [25][26][51][52]. Interestingly, M2 mMPs are not as beneficial when delivered early [ Hsieh PL et al, Unpublished Data ].…”

Skeletal muscle regeneration involves macrophage-myoblast bonding

“…Moreover, pro-inflammatory macrophages also improved migration and delayed differentiation of the myogenic precursors, as opposed to the anti-inflammatory subpopulation, which facilitated alignment, fusion and further myoblast growth. 4 Similar kinetics of macrophage subtypes and adult myogenesis sequences were demonstrated during normal regeneration in human samples. 5 Though, most studies looking at the involvement of macrophages in the regeneration process have focused on soluble molecules like prostaglandins, cytokines and chemokines, 6 only few reports assumed the importance of intercellular contacts.…”

Shared signaling systems in myeloid cell-mediated muscle regeneration

“…In vitro observations showed similar relationships between macrophage phenotype and stages of myogenesis. Cultures of satellite cells with M1 macrophages increased satellite cell proliferation (Bencze et al, 2012), but decreased the proportion of Box 1. Indices of muscle regeneration Muscle regeneration can be assessed based on the extent or rate at which damaged muscle recovers its normal structure and function.…”

“…Interestingly, at 5 days post-injection, the great majority of the transplanted macrophages were CD206 + (also known as Mrc1) M2 macrophages, suggesting that bias toward the M2 phenotype might be beneficial. However, an additional investigation showed that co-injection of muscle cells with human M1 macrophages into immunodeficient [Rag2 −/− γC −/− (also known as Il2rg)] mdx mice improved the proliferation and dispersal of transplanted muscle cells, although co-injection with M2 macrophages did not affect these outcomes (Bencze et al, 2012). In that study, macrophages were activated to the M1 phenotype with LPS and IFNγ or to the M2 phenotype with dexamethasone and IL-10, prior to injection.…”