Fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH regulation of adipogenesis.

Milica Marinkovic,Gianni Cesareni,Simone Vumbaca,Alessandro Zuccotti,Claudia Fuoco,Theodora Pavlidou,Andrea Cerquone Perpetuini,Giulio Giuliani,Francesca Sacco,Elisa Micarelli,Matthias Mann,Cesare Gargioli,Federica Riccio,Alessio Reggio,Filomena Spada,Luisa Castagnoli,Lucia Lisa Petrilli

doi:10.26508/lsa.201900437

Abstract

Fibro-adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin-deficient mdx mice are insensitive to this control mechanism. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild-type and mdx mice suggested that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in mdx FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.

Highlights

Skeletal muscle regeneration is a highly orchestrated process involving a variety of mononuclear cell populations that are either resident or attracted to the injured tissue by inflammatory signals (Bentzinger et al, 2013).A stem cell population residing under the myofiber basal lamina, satellite cells (SCs), is the main source of myoblasts during regeneration (Wang & Rudnicki, 2012; Yin et al, 2013)
To investigate the molecular basis of this phenomenon, we focused on the NOTCH pathway because (i) it is activated by cell–cell contact (Andersson & Lendahl, 2014), (ii) it is a known regulator of stem cell quiescence (Koch et al, 2013), and (iii) it plays a fundamental role in muscle regeneration (Mourikis & Tajbakhsh, 2014)
Preparation, the mdx and ctx preparations displayed a second peak of cells expressing higher levels of CD34 and/or SCA1 (Fig 1B), the second population being more numerous in the ctx fibro-adipogenic progenitors (FAPs) preparations

Summary

Introduction

Skeletal muscle regeneration is a highly orchestrated process involving a variety of mononuclear cell populations that are either resident or attracted to the injured tissue by inflammatory signals (Bentzinger et al, 2013).A stem cell population residing under the myofiber basal lamina, satellite cells (SCs), is the main source of myoblasts during regeneration (Wang & Rudnicki, 2012; Yin et al, 2013). Skeletal muscle regeneration is a highly orchestrated process involving a variety of mononuclear cell populations that are either resident or attracted to the injured tissue by inflammatory signals (Bentzinger et al, 2013). Toward the end of the repair process, excessive FAPs, which are generated during the expansion phase, are removed while the remaining FAPs return to the initial quiescent state (Joe et al, 2010; Uezumi et al, 2010; Pretheeban et al, 2012; Lemos et al, 2015). Instead of returning to the quiescent state, they rather differentiate causing fibrosis and fat infiltrations (Rodeheffer, 2010; Uezumi et al, 2010, 2011; Stumm et al, 2018)

Methods

Results

Conclusion