Evolving Roles of Muscle-Resident Fibro-Adipogenic Progenitors in Health, Regeneration, Neuromuscular Disorders, and Aging

Abstract

Normal skeletal muscle functions are affected following trauma, chronic diseases, inherited neuromuscular disorders, aging, and cachexia, hampering the daily activities and quality of life of the affected patients. The maladaptive accumulation of fibrous intramuscular connective tissue and fat are hallmarks of multiple pathologies where chronic damage and inflammation are not resolved, leading to progressive muscle replacement and tissue degeneration. Muscle-resident fibro-adipogenic progenitors are adaptable stromal cells with multilineage potential. They are required for muscle homeostasis, neuromuscular integrity, and tissue regeneration. Fibro-adipogenic progenitors actively regulate and shape the extracellular matrix and exert immunomodulatory functions via cross-talk with multiple other residents and non-resident muscle cells. Remarkably, cumulative evidence shows that a significant proportion of activated fibroblasts, adipocytes, and bone-cartilage cells, found after muscle trauma and disease, descend from these enigmatic interstitial progenitors. Despite the profound impact of muscle disease on human health, the fibrous, fatty, and ectopic bone tissues' origins are poorly understood. Here, we review the current knowledge of fibro-adipogenic progenitor function on muscle homeostatic integrity, regeneration, repair, and aging. We also discuss how scar-forming pathologies and disorders lead to dysregulations in their behavior and plasticity and how these stromal cells can control the onset and severity of muscle loss in disease. We finally explore the rationale of improving muscle regeneration by understanding and modulating fibro-adipogenic progenitors' fate and behavior.

Keywords: aging; duchenne muscular dystrophy (DMD); extracellular matrix (ECM); macrophages; muscle FAPs; muscle regeneration; muscle stem cells (MuSCs); skeletal muscle fibrosis.

FIGURE 1

Fibro-adipogenic progenitors are essential and required for efficient skeletal muscle regeneration and homeostatic neuromuscular integrity. Skeletal muscle FAPs are abundant stromal cells, reside within the connective tissue, and lie near the nerve parenchyma and NMJs in healthy muscles and homeostatic conditions. Conditional ablation of FAP+ cells using diphtheria toxin resulted in delayed regeneration and reduced numbers of MuSCs and HCs. In homeostasis and non-damaged muscles, widespread ablation of FAPs causes muscle atrophy, impair Schwann cell, and MuSC behavior and abundance. Impaired NMJ architecture and partial and complete muscle denervation also result from FAP cell ablation without damage. MuSC, muscle stem cell; HCs, hematopoietic cells; NMJ, neuromuscular junction. Motoneuron and Schwann cells are not shown in the middle panel because of space constraints and improved readability.

FIGURE 2

The dynamic flux of muscle stromal, satellite and immune cells cellular flux responds to acute and chronic injury. (Top) Muscle regeneration is orchestrated by a synchronous array and flux of several muscle-resident and non-resident cells that interplay to maintain muscle structural integrity and function following injury. Followed the quick and early immune response of resident and non-resident macrophages, neutrophils, and eosinophils; FAPs and MuSCs rapidly activate and proliferate around day 3–5 post-damage. Here, FAPs provide constant support to myogenesis and actively participate in matrix remodeling. This process occurs in parallel with macrophage skewing, and the presence of regulatory Ts-cells follows it. Later, their lineage cells start committing and differentiating. By around day 21 post-injury, injured muscles have regenerated, and damage-induced cellular flux returned to steady-state levels. (Bottom) Chronic muscle injury is characterized by progressive muscle degeneration and a dysregulated burst of immune, MuSC, and FAP cells, among other cell types (not shown here for simplification purposes). Several neuromuscular disorders and muscle diseases are often characterized by chronic cycles of muscle degeneration and regeneration. However, there is less knowledge and characterizations about these cellular compartments’ behavior compared to single rounds of injury. Aging and prolonged disease states cause MuSC exhaustion, and FAPs seem to respond similarly. To date, Duchenne muscular dystrophy (DMD) represents the better-characterized muscle disease, but it is unknown whether this gained knowledge can be applied to other disease settings. Tregs, muscle regulatory T-cell; FAP, fibro-adipogenic progenitor; MuSC, muscle stem cell; MØ, macrophage.

FIGURE 3

FAP-immune cell cross-talk and secretory flux in regeneration and disease. (Top) FAPs and several immune cell types are involved in regulating efficient muscle regeneration following injury. Th1 and Th2 immune cell populations characterize the immune response. This coordinated FAP-immune cell interaction occurs through the secretion of several pro-regenerative and inflammatory cues from both stromal compartments. All of this facilitates transient ECM remodeling by FAPs that promotes muscle regeneration. (Bottom) On the contrary, neuromuscular disorders and chronic trauma drive the muscle milieu into an aberrant state that usually supports repairing the damaged muscles. Gradually, persistent inflammation tip points the regenerative muscle potential toward muscle degeneration, causes over-activation of FAPs, increases TGF-β levels beyond a regenerative state, and leads to FAP-mediated tissue replacement by fibrous, fat and bone-like tissues. Owing to this, affected muscles reach a state of pathogenic positive feedback loop where damage-driven fibro-fatty-bone infiltration enhances tissue malfunctioning and failure.

FIGURE 4

Fibro-adipogenic progenitors as central drivers of muscle pathology and fibro-fatty infiltration. Skeletal muscles have high regenerative capabilities after a single round of injury, which progressively diminishes following chronic damage. Hence, chronic injury primes the tissue into a state of progressive degeneration. In homeostasis, a high proportion of fibro-adipogenic progenitors are perivascular cells and remain quiescent. Injury activates FAPs and induces their expansion and differentiation into several mesenchymal lineages, including activated fibroblasts, adipocytes, and bone-like cells. Activated FAPs and their lineage derived fibroblasts produce increased amounts of extracellular matrix (ECM), leading to connective tissue hyperplasia and poorer outcomes for patients. In several traumas and pathology, the adipogenic differentiation of FAPs also impairs muscle function and integrity. Muscle degeneration associates with an increased number of FAPs, activated TGF-β signaling and enhanced fibrosis. Chondrogenic and osteogenic FAP differentiation are not depicted to simplify the cartoon.

FIGURE 5

Impaired FAP numbers, behavior, and fate in aged muscles. (A) Sarcopenic and cachexic muscles have altered muscular integrity and structure, impaired neuromuscular communication, reduced regenerative capacities, enhanced fibrosis, and altered FAP number, fate, and behavior. These structural, cellular, and molecular age-related changes are associated with increased muscle frailty and muscle mass loss. (B) FAP-derived molecules regulate neuromuscular integrity, muscle mass, and MuSC expansion and fate. These include Follistatin, WISP1, and BMP3B. Aging impairs FAP proliferation and expansion, whereas it promotes fibrogenesis over adipogenesis.