Interactions between muscle stem cells, mesenchymal-derived cells and immune cells in muscle homeostasis, regeneration and disease

Abstract

Recent evidence has revealed the importance of reciprocal functional interactions between different types of mononuclear cells in coordinating the repair of injured muscles. In particular, signals released from the inflammatory infiltrate and from mesenchymal interstitial cells (also known as fibro-adipogenic progenitors (FAPs)) appear to instruct muscle stem cells (satellite cells) to break quiescence, proliferate and differentiate. Interestingly, conditions that compromise the functional integrity of this network can bias muscle repair toward pathological outcomes that are typically observed in chronic muscular disorders, that is, fibrotic and fatty muscle degeneration as well as myofiber atrophy. In this review, we will summarize the current knowledge on the regulation of this network in physiological and pathological conditions, and anticipate the potential contribution of its cellular components to relatively unexplored conditions, such as aging and physical exercise.

Figure 1

(a) Schematic illustration of localization of satellite cell, FAP, macrophage and eosinophil in relation to muscle fibers and capillaries. Compare with image in b. Sizes of individual cells are not drawn to scale. (b) Immunohistochemical staining of human muscle biopsy cross-section with antibodies against Pax7 (brown), laminin (green) and MHCI (red). Nuclei are stained blue with DAPI

Figure 2

Schematic illustration showing cellular interactions in skeletal muscle between immune cells, SCs, FAPs and endothelial cells with indication of some known mediators of these interactions (based on results from Heredia et al., Mozzetta et al., Tardif et al., Moyer and Wagner and Snijders et al.). For further details see text. Abbreviations: HGF, hepatocyte growth factor; IL, interleukin; IGF-1, insulin-like growth factor 1; NO, nitric oxide; TNFα, tumor necrosis factor α; TGFβ, transforming growth factor β

Figure 3

Mononuclear cell isolation procedure from skeletal muscle composed of mechanical and enzymatic digestion, filtration, blocking, antigen labeling and finally multiple parameter FACS to sort out selected cell populations. (A) Representative plots showing FACS strategy to sort lineage-negative (Ter119⁻ CD45⁻ CD31⁻) SCs (α7 integrin⁺) and FAPs (Sca1⁺) as well as lineage-positive macrophages (MPs, CD11b⁺ F480⁺) from skeletal muscle of healthy (a) and mdx (b) mice. (B) Representative images of adipogenic (Oil Red O (a)) and fibrogenic (α-smooth muscle actin (b)) phenotype of FAPs during differentiation

Figure 4

HDACs control an epigenetic network that determines FAP ability to support either regeneration or fibro-adipogenic degeneration. Inhibition of HDAC induced an upregulation of BAF60c that is engaged in the SWI/SNF complex leading to an increase of the myomiR expression and ultimately promoting a pro-myogenic phenotype in FAPs

Figure 5

Schematic illustration showing potential role of FAP-SC and their interplay in muscle: atrophy (as observed with aging and disease), hypertrophy and insulin sensitivity. IL-4, interleukin-4; IMAT, intramuscular adipose tissue; T2D, type 2 diabetes