Redressing the interactions between stem cells and immune system in tissue regeneration

Abstract

Skeletal muscle has an extraordinary regenerative capacity reflecting the rapid activation and effective differentiation of muscle stem cells (MuSCs). In the course of muscle regeneration, MuSCs are reprogrammed by immune cells. In turn, MuSCs confer immune cells anti-inflammatory properties to resolve inflammation and facilitate tissue repair. Indeed, MuSCs can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory ability, including effects primed by interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). At the molecular level, the tryptophan metabolites, kynurenine or kynurenic acid, produced by indoleamine 2,3-dioxygenase (IDO), augment the expression of TNF-stimulated gene 6 (TSG6) through the activation of the aryl hydrocarbon receptor (AHR). In addition, insulin growth factor 2 (IGF2) produced by MuSCs can endow maturing macrophages oxidative phosphorylation (OXPHOS)-dependent anti-inflammatory functions. Herein, we summarize the current understanding of the immunomodulatory characteristics of MuSCs and the issues related to their potential applications in pathological conditions, including COVID-19.

Keywords: Immune cells; Immunomodulation; MuSCs; Muscle repair; Tissue regeneration.

Fig. 1

The reciprocal interaction between MuSCs and immune cells during muscle regeneration. Trauma to muscle evokes dramatic immune challenge. Within hours, damaged muscle tissue experiences mast cell degranulation, invasion by neutrophils, infiltration by M1 macrophages, and trafficking of effector T cells. These immune cells condition the inflammatory environment that is enriched with pro­inflammatory cytokines, including IFN-γ and TNF-α, and direct rapid expansion of the MuSC population. The shift of macrophage phenotype functionally couples with the transition of stages of myogenesis. IGF1 modulates autocrine polarization of pro-inflammatory macrophages towards a M2 phenotype. Treg cells also promote the transition of macrophage phenotype through paracrine action of IL-10. Furthermore, MuSCs could orchestrate inflammatory microenvironments through directing the switch towards anti-inflammatory macrophages via the action of IGF2. The resolution of inflammation through multiple mechanisms drives the later stages of MuSC differentiation. Thus, the bidirectional interaction between MuSCs and immune cells determines the course and outcome of muscle regeneration

Fig. 2

The immunomodulatory properties of MuSCs during colon inflammation. The resolution of inflammation allows tissue to return to homeostasis. The immunomodulatory properties of MuSCs are required from this process. On the one hand, MuSCs can act on maturing macrophages and confer them with anti-inflammatory properties via IGF2 secretion, thus ameliorating DSS-induced colitis and facilitating tissue repair. On the other hand, inflammatory cytokines-licensed MuSCs, particularly with IFN-γ and TNF-α, can also alleviate DSS-induced colitis through IDO metabolites-mediated TSG6 production, which mediates the switch of macrophages from a M1 to a M2 phenotype