Interleukin-15 facilitates muscle regeneration through modulation of fibro/adipogenic progenitors

Abstract

BackgroundChronic muscle injury is characteristics of fatty infiltration and fibrosis. Recently, fibro/adipogenic progenitors (FAPs) were found to be indispensable for muscular regeneration while were also responsible for fibrosis and fatty infiltration in muscle injury. Many myokines have been proven to regulate the adipose or cell proliferation. Because the fate of FAPs is largely dependent on microenvironment and the regulation of myokines on FAPs is still unclear. We screened the potential myokines and found Interleukin-15 (IL-15) may regulate the fatty infiltration in muscle injury. In this study, we investigated how IL-15 regulated FAPs in muscle injury and the effect on muscle regeneration.MethodsCell proliferation assay, western blots, qRT-PCR, immunohistochemistry, flow cytometric analysis were performed to investigate the effect of IL-15 on proliferation and adipogensis of FAPs. Acute muscle injury was induced by injection of glycerol or cardiotoxin to analyze how IL-15 effected on FAPs in vivo and its function on fatty infiltration or muscle regeneration.ResultsWe identified that the expression of IL-15 in injured muscle was negatively associated with fatty infiltration. IL-15 can stimulate the proliferation of FAPs and prevent the adipogenesis of FAPs in vitro and in vivo. The growth of FAPs caused by IL-15 was mediated through JAK-STAT pathway. In addition, desert hedgehog pathway may participate in IL-15 inhibiting adipogenesis of FAPs. Our study showed IL-15 can cause the fibrosis after muscle damage and promote the myofiber regeneration. Finally, the expression of IL-15 was positively associated with severity of fibrosis and number of FAPs in patients with chronic rotator cuff tear.ConclusionsThese findings supported the potential role of IL-15 as a modulator on fate of FAPs in injured muscle and as a novel therapy for chronic muscle injury.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0251-0) contains supplementary material, which is available to authorized users.

Rotator Cuff Fibro‐Adipogenic Progenitors Demonstrate Highest Concentration, Proliferative Capacity, and Adipogenic Potential Across Muscle Groups

“…In addition, our study found significantly more adipogenesis and increased FAP percentage in SS compared with TA after the same glycerol‐induced injury of each muscle. Kang et al found that the adipocyte area increased to approximately 6% in mouse TA muscle 7 days after glycerol injection using triple the dose used in our study. Lukjanenko et al showed similar results as our study regarding TA FI with approximately 1% adipocyte area at 2 weeks using a comparable glycerol dose.…”

“…Intramuscular glycerol injection has been shown to induce muscle FI as an established model of muscle injury . To assess for differences in adipogenic and proliferative potential of FAPs in vivo across muscle groups after same FI‐inducing injury, 30 µl of 50% glycerol in 0.9% saline was injected into the mid‐bellies of the SS and tibialis anterior muscles, respectively, in a third group of PDGFRα‐eGFP reporter mice ( n = 4 per subgroup).…”

Role of Metabolic Stress and Exercise in Regulating Fibro/Adipogenic Progenitors

“…Metabolic stress has been linked to FAP accumulation and fibro/adipogenic differentiation (Dammone et al, 2018;Gorski et al, 2018;Kang et al, 2018;Buras et al, 2019). Using several different genetic and diet-induced mouse models of diabetes, Mogi et al (2016) demonstrated that ectopic adipocyte accumulation in skeletal muscle was derived from PDGFRα + progenitors.…”

Biomaterial and stem cell‐based strategies for skeletal muscle regeneration

“…For instance, by inhibiting TGF‐β1, FAPs were shown to become apoptotic in the presence of macrophages, which correlated with decreased fibrosis in vivo . Cytokines such as IL‐4 and IL‐15 were shown to prevent FAPs from undergoing adipogenic differentiation . Future studies should focus on elucidating the diverse differentiation mechanisms of FAPs.…”

“…101 Cytokines such as IL-4 and IL-15 were shown to prevent FAPs from undergoing adipogenic differentiation. 102,103 Future studies should focus on elucidating the diverse differentiation mechanisms of FAPs. Identification of precise factors and molecules that can modulate FAP activity to promote myogenic regeneration without fibrotic and fatty tissue deposition are likely to offer great therapeutic benefits to aging, diseased, or severely injured skeletal muscle.…”