Depletion of CD206 M2-like Macrophages Induces Fibro-adipogenic Progenitors Activation and Muscle Regeneration

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Nov 21

PMID 36411280

Authors

Allah Nawaz

Muhammad Bilal

Shiho Fujisaka

Tomonobu Kado

Muhammad Rahil Aslam

Saeed Ahmed

Keisuke Okabe

Yoshiko Igarashi

Yoshiyuki Watanabe

Takahide Kuwano

Koichi Tsuneyama

Ayumi Nishimura

Yasuhiro Nishida

Seiji Yamamoto

Masakiyo Sasahara

Johji Imura

Hisashi Mori

Martin M Matzuk

Fujimi Kudo

Ichiro Manabe

Akiyoshi Uezumi

Takashi Nakagawa

Yumiko Oishi

Kazuyuki Tobe

Affiliations

Soon will be listed here.

Abstract

Muscle regeneration requires the coordination of muscle stem cells, mesenchymal fibro-adipogenic progenitors (FAPs), and macrophages. How macrophages regulate the paracrine secretion of FAPs during the recovery process remains elusive. Herein, we systemically investigated the communication between CD206 M2-like macrophages and FAPs during the recovery process using a transgenic mouse model. Depletion of CD206 M2-like macrophages or deletion of CD206 M2-like macrophages-specific TGF-β1 gene induces myogenesis and muscle regeneration. We show that depletion of CD206 M2-like macrophages activates FAPs and activated FAPs secrete follistatin, a promyogenic factor, thereby boosting the recovery process. Conversely, deletion of the FAP-specific follistatin gene results in impaired muscle stem cell function, enhanced fibrosis, and delayed muscle regeneration. Mechanistically, CD206 M2-like macrophages inhibit the secretion of FAP-derived follistatin via TGF-β signaling. Here we show that CD206 M2-like macrophages constitute a microenvironment for FAPs and may regulate the myogenic potential of muscle stem/satellite cells.

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References

Lee S, Lee Y, Zimmers T, Soleimani A, Matzuk M, Tsuchida K . Regulation of muscle mass by follistatin and activins. Mol Endocrinol. 2010; 24(10):1998-2008. PMC: 2954636. DOI: 10.1210/me.2010-0127. View

Nawaz A, Aminuddin A, Kado T, Takikawa A, Yamamoto S, Tsuneyama K . CD206 M2-like macrophages regulate systemic glucose metabolism by inhibiting proliferation of adipocyte progenitors. Nat Commun. 2017; 8(1):286. PMC: 5561263. DOI: 10.1038/s41467-017-00231-1. View

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

Ruffell D, Mourkioti F, Gambardella A, Kirstetter P, Lopez R, Rosenthal N . A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc Natl Acad Sci U S A. 2009; 106(41):17475-80. PMC: 2762675. DOI: 10.1073/pnas.0908641106. View

Mann C, Perdiguero E, Kharraz Y, Aguilar S, Pessina P, Serrano A . Aberrant repair and fibrosis development in skeletal muscle. Skelet Muscle. 2011; 1(1):21. PMC: 3156644. DOI: 10.1186/2044-5040-1-21. View

Nawaz A, Mehmood A, Kanatani Y, Kado T, Igarashi Y, Takikawa A . Sirt1 activator induces proangiogenic genes in preadipocytes to rescue insulin resistance in diet-induced obese mice. Sci Rep. 2018; 8(1):11370. PMC: 6063897. DOI: 10.1038/s41598-018-29773-0. View

Contreras-Shannon V, Ochoa O, Reyes-Reyna S, Sun D, Michalek J, Kuziel W . Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2-/- mice following ischemic injury. Am J Physiol Cell Physiol. 2006; 292(2):C953-67. DOI: 10.1152/ajpcell.00154.2006. View

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi A, Tanaseichuk O . Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019; 10(1):1523. PMC: 6447622. DOI: 10.1038/s41467-019-09234-6. View

Trendelenburg A, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass D . Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol. 2009; 296(6):C1258-70. DOI: 10.1152/ajpcell.00105.2009. View

10.

Nawaz A, Tobe K . M2-like macrophages serve as a niche for adipocyte progenitors in adipose tissue. J Diabetes Investig. 2019; 10(6):1394-1400. PMC: 6825922. DOI: 10.1111/jdi.13114. View

11.

Joe A, Yi L, Natarajan A, Le Grand F, So L, Wang J . Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol. 2010; 12(2):153-63. PMC: 4580288. DOI: 10.1038/ncb2015. View

12.

Choi K, Kashyap P, Dutta N, Stoltz G, Ordog T, Shea Donohue T . CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice. Gastroenterology. 2010; 138(7):2399-409, 2409.e1. PMC: 2883675. DOI: 10.1053/j.gastro.2010.02.014. View

13.

Chen J, Walton K, Hagg A, Colgan T, Johnson K, Qian H . Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease. Proc Natl Acad Sci U S A. 2017; 114(26):E5266-E5275. PMC: 5495232. DOI: 10.1073/pnas.1620013114. View

14.

Lukjanenko L, Karaz S, Stuelsatz P, Gurriaran-Rodriguez U, Michaud J, Dammone G . Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors. Cell Stem Cell. 2019; 24(3):433-446.e7. PMC: 6408230. DOI: 10.1016/j.stem.2018.12.014. View

15.

Ratnayake D, Nguyen P, Rossello F, Wimmer V, Tan J, Galvis L . Macrophages provide a transient muscle stem cell niche via NAMPT secretion. Nature. 2021; 591(7849):281-287. DOI: 10.1038/s41586-021-03199-7. View

16.

Roubenoff R, Hughes V . Sarcopenia: current concepts. J Gerontol A Biol Sci Med Sci. 2000; 55(12):M716-24. DOI: 10.1093/gerona/55.12.m716. View

17.

Ignotz R, Massague J . Type beta transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts. Proc Natl Acad Sci U S A. 1985; 82(24):8530-4. PMC: 390950. DOI: 10.1073/pnas.82.24.8530. View

18.

Magalhaes M, Smith P, Portman J, Jackson-Jones L, Bain C, Ramachandran P . Role of Tim4 in the regulation of ABCA1 adipose tissue macrophages and post-prandial cholesterol levels. Nat Commun. 2021; 12(1):4434. PMC: 8295389. DOI: 10.1038/s41467-021-24684-7. View

19.

Backdahl J, Franzen L, Massier L, Li Q, Jalkanen J, Gao H . Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin. Cell Metab. 2021; 33(9):1869-1882.e6. DOI: 10.1016/j.cmet.2021.07.018. View

20.

Nishida Y, Nawaz A, Kado T, Takikawa A, Igarashi Y, Onogi Y . Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway. J Cachexia Sarcopenia Muscle. 2020; 11(1):241-258. PMC: 7015247. DOI: 10.1002/jcsm.12530. View