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. 2018 Jul 20;16(1):42.
doi: 10.1186/s12964-018-0251-0.

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

Xia Kang  1 , Ming-Yu Yang  1 , You-Xing Shi  1 , Mei-Ming Xie  1 , Min Zhu  1 , Xiao-Long Zheng  1 , Chen-Ke Zhang  1 , Zi-Lu Ge  1 , Xu-Ting Bian  1 , Jing-Tong Lv  1 , Yun-Jiao Wang  1 , Bing-Hua Zhou  2 , Kang-Lai Tang  3
Affiliations

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

Xia Kang et al. Cell Commun Signal. .

Abstract

Background: Chronic 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.

Methods: Cell 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.

Results: We 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.

Conclusions: These 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.

Keywords: Fatty infiltration; Fibro/adipogenic progenitor; Fibrosis; IL-15; Muscle injury; Rotator cuff tear.

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Conflict of interest statement

Ethics approval and consent to participate

Ethical approval to conduct the study was obtained from The Ethical Committee of Southwest Hospital (Third Military Medical University, Chongqing). All necessary consent was obtained from all participants.

Consent for publication

Consent for publication was obtained from patients.

Competing interests

The authors declare that they have no competing interests. The authors declare that this manuscript has not been submitted or is not simultaneously being submitted elsewhere, and that no portion of the data has been or will be published in proceedings or transactions of meetings or symposium volumes.

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Figures

Fig. 1
Fig. 1
The level of IL-15 is negatively associated with fatty infiltration in chronic muscle injury. After injection of glycerol in tibialis anterior, the pathological changes of myofibers (a) and fatty infiltration (b) were examined by immunofluorescene, an antibody against adipocyte biomarker perilipin were used to detect the adipose formation in injured mice. c The mRNA level of candidate myokines in injured muscle on 0 days and 7 dpi. Were analyzed using real-time PCR. Scale bars, 20 μm (a, b)
Fig. 2
Fig. 2
IL-15 inhibits the adipogenesis of FAPs both in vivo and in vitro. a Immunofluorescence for fatty infiltration after administration of IL-15 in injured muscles 7 dpi. Scale bars, 20 μm. b Quantifications of adipose occupied area (shown in percentage) in injured muscles 7 dpi with glycerol injection. c Real-time PCR for adipogenic biomarkers (c/ebpα, pparγ and FABP4) in whole injured muscles 7 dpi with glycerol injection. d The effect of IL-15 on adipogenesis of FAPs was detected by Oil Red O staining in vitro. Scale bars, 100 μm (top), 40 μm (bottom). e Quantifications of Oil Red O occupied area (shown in percentage). f qPCR analysis of DHH and TIMP3 in purified FAPs from injured muscles 7 dpi
Fig. 3
Fig. 3
IL-15 stimulates proliferation of FAPs both in vivo and in vitro. a A schematic showing the experiment in vivo: IL-15 (or combination with Jak inhibitor) was administered from 3dpi to 5 dpi and samples were sectioned on 7 dpi (top). Activated FAPs were detected by staining Ki67 (bottom). Scale bars, 20 μm. b Quantifications of percentage of PDGFRα+Ki67+ FAPs in total FAPs. c The ability of proliferation of FAPs in the presence of IL-15 (or combination with Jak inhibitor) detected by BrdU staining. d Quantifications of percentage of BrdU+ FAPs in total FAPs. e Western blots for activation of Jak-STAT pathways after stimulated by IL-15 with/without inhibitor and (f) quantity analysis. g FITC-Annexin-V/PI assay for apoptosis of FAPs after stimulated by IL-15 for 48 h. Values not sharing a common small letter differ significantly (p < 0.05). Abbreviations: Gly, glycerol; I, Inhibitor
Fig. 4
Fig. 4
Administration of IL-15 enhances collagen deposition in injured muscles. a A schematic showing the experiment in vivo: IL-15 (or combination with Jak inhibitor) was administered from 1dpi to 3 dpi and samples were sectioned on 5 dpi. b Immunofluorescence for collagen I after administration of IL-15 in injured muscle 5 dpi. Scale bar, 20 μm. c Quantification of collagen deposition area (shown in percentage). d qPCR analysis of fibrosis-associated biomarkers, Fn1 and collagen I, in injured muscle with glycerol injection 5 dpi. Abbreviations: Gly, glycerol; Colla 1, Collagen I
Fig. 5
Fig. 5
IL-15 can facilitate regeneration of myofibers in injured muscles. a A shcematic showing the experiment in vivo: IL-15 was administered from 1dpi to 3 dpi and samples were sectioned on 8 dpi. b Immunofluorescence for myofibers 8 days after glycerol injection with administration of IL-15 by staining phalloidine. c Quantifications of average cross-sectional area of myofibers with administration of IL-15. d Immunofluorescence for Laminin α2 and Hoechst in injured muscle 8 dpi with administration of IL-15. e Quantifications of percentages of number of myofibers with centrally located nuclei. f Number of nuclei present in myofibers with administration of IL-15. Abbreviations: Gly, glycerol; Colla 1, Collagen I
Fig. 6
Fig. 6
The expression of IL-15 is positively correlated with number of FAPs and collagen deposition in subjects with rotator cuff tear. a Immunofluorescence for PDGFRα and Laminin in muscles from subjects with RCT. b Quantification of number of FAPs in muscles from subjects with RCT. c Immunofluorescence for Collagen Iin muscles from subjects with RCT. d Quantification of percentage of collagen deposition area in muscles from subjects with RCT. e qPCT analysis of mRNA expression of IL-15 in samples from patients with RCT. f Pearson’s correlation analysis for mRNA level of IL-15 and number of FAPs in samples from patients with RCT. g Pearson’s correlation analysis for mRNA level of IL-15 and percentage of area of collagen deposition in samples from patients with RCT
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