Exploring the therapeutic potential of fibroadipogenic progenitors in muscle disease

Abstract

Skeletal muscle relies on its inherent self-repair ability to withstand continuous mechanical damage. Myofiber-intrinsic processes facilitate the repair of damage to sarcolemma and sarcomeres, but it is the coordinated interaction between muscle-resident satellite and stromal cells that are crucial in the regeneration of muscles to replace the lost muscle fibers. Fibroadipogenic progenitors (FAPs), are muscle-resident mesenchymal cells that are notable for their role in creating the dynamic stromal niche required to support long-term muscle homeostasis and regeneration. While FAP-mediated extracellular matrix formation and the establishment of a homeostatic muscle niche are essential for maintaining muscle health, excessive accumulation of FAPs and their aberrant differentiation leads to the fibrofatty degeneration that is a hallmark of myopathies and muscular dystrophies. Recent advancements, including single-cell RNA sequencing and in vivo analysis of FAPs, are providing deeper insights into the functions and specialization of FAPs, shedding light on their roles in both health and disease. This review will explore the above insights, discussing how FAP dysregulation contributes to muscle diseases. It will offer a concise overview of potential therapeutic interventions targeting FAPs to restore disrupted interactions among FAPs and muscle-resident cells, ultimately addressing degenerative muscle loss in neuromuscular diseases.

Keywords: adipogenesis; fibroadipogenic; fibrosis; mesenchymal stem cells; muscle; muscular dystrophy; regeneration.

Figure 1:. Illustration of the cellular players that drive muscle re/degeneration.

The schematic shows the three class of muscle-resident mononuclear cells that play a part in the repair or loss of injured skeletal muscle. These include the Inflammatory cells that migrate from blood to the site of injury to initiate the repair process, the MuSCs that undergo myogenic fusion to form the multinucleated myofibers, and the FAPs that proliferate and differentiate the form the ECM to support the regenerated myofibers. However, aberrant inflammatory or myogenic response in diseases can trigger the FAPs to adopt alternate differentiation program including osteogenesis, fibrogenesis, and/or adipogenesis that eventually lead to these degenerative tissue matrix and loss of muscle function.

Figure 2:. Cellular choreography during acute repair stages of injured healthy and dystrophic muscle.

The schematic shows the contrast between the well-coordinated regenerative response following a bout of acute injury in healthy muscle vs dysregulation of this process in dystrophic muscle. Muscle regeneration is a highly dynamic process and the static images here represent events starting prior to onset of dystrophic symptoms or any muscle injury and in the days following injury grouped into immediately (1-2 days), early (3-5 days), and late (beyond 7 days) post injury. In healthy muscle, inflammatory cells enter the site rapidly after myofiber injury to clear debris from damaged myofibers and the basement membrane. During the early stages of repair, the injury site becomes inflamed and supports MuSC and FAPs proliferation and onset of their differentiation to begin reforming the lost myofiber and basement membrane respectively. The niche then transitions over the next 1-2 weeks to complete regeneration of the lost myofiber and clearance of FAPs to return the muscle to its homeostatic state. In dystrophic muscle, this process is dysregulated leading to incomplete repair which is compounded by subsequent rounds of damage and regeneration deficit that causes chronic activation of macrophages and failure of the injury site to sequentially transition from an inflammatory to a resolving niche. This loss of cellular choreography and associated cellular cues cause FAPs to proliferate excessively and accumulate in the muscle by failed clearance and begin their differentiation into fibroblasts or adipocytes which replaces the lost myofibers with fibrotic or adipogenic deposits.