Six1 regulates stem cell repair potential and self-renewal during skeletal muscle regeneration

Macrophage gene expression determines phagocyte responses and effector functions. Macrophage plasticity has been mainly addressed in in vitro models that do not account for the environmental complexity observed in vivo. In this study, we show that microarray gene expression profiling revealed a highly dynamic landscape of transcriptomic changes of Ly6CposCX3CR1lo and Ly6CnegCX3CR1hi macrophage populations during skeletal muscle regeneration after a sterile damage. Systematic gene expression analysis revealed that the time elapsed, much more than Ly6C status, was correlated with the largest differential gene expression, indicating that the time course of inflammation was the predominant driving force of macrophage gene expression. Moreover, Ly6Cpos/Ly6Cneg subsets could not have been aligned to canonical M1/M2 profiles. Instead, a combination of analyses suggested the existence of four main features of muscle-derived macrophages specifying important steps of regeneration: 1) infiltrating Ly6Cpos macrophages expressed acute-phase proteins and exhibited an inflammatory profile independent of IFN-γ, making them damage-associated macrophages; 2) metabolic changes of macrophages, characterized by a decreased glycolysis and an increased tricarboxylic acid cycle/oxidative pathway, preceded the switch to and sustained their anti-inflammatory profile; 3) Ly6Cneg macrophages, originating from skewed Ly6Cpos cells, actively proliferated; and 4) later on, restorative Ly6Cneg macrophages were characterized by a novel profile, indicative of secretion of molecules involved in intercellular communications, notably matrix-related molecules. These results show the highly dynamic nature of the macrophage response at the molecular level after an acute tissue injury and subsequent repair, and associate a specific signature of macrophages to predictive specialized functions of macrophages at each step of tissue injury/repair.

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“…1). They represent the majority of macrophages at this time point (∼1800 macrophages/mg muscle [13] (17,18) (Fig. 1).…”

Section: Cx3cr1mentioning

confidence: 94%

Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue Repair

Varga

Mounier

Horváth

et al. 2016

The Journal of Immunology

156

212

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“…Tibialis anterior and EDL muscles of P6, P21 or 6-week-old male mice from each genotype were dissected and fixed for 4 h at 4°C in 4% paraformaldehyde (PFA) and washed in PBS as described previously (Le Grand et al, 2012). After incubation in PBS and 10% sucrose overnight at 4°C, samples were incubated in PBS with 10% gelatin and 10% sucrose, then 10% gelatin and frozen in isopentane cooled by liquid nitrogen.…”

Section: Histology and Immunostainingmentioning

confidence: 99%

“…Primary myoblasts were isolated from limb muscles of P21 and 6-week-old male mice as described previously (Le Grand et al, 2012). For the adult 129SV/Pas wt and H19 Δ3 cultures, two mice for each genotype were dissected.…”

Section: Primary Myoblast Isolation and Cell Proliferation Assaymentioning

confidence: 99%

H19 controls reactivation of the imprinted gene network during muscle regeneration

et al. 2016

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The H19 locus controls fetal growth by regulating expression of several genes from the imprinted gene network (IGN). H19 is fully repressed after birth, except in skeletal muscle. Using loss-of-function H19 Δ3 mice, we investigated the function of H19 in adult muscle. Mutant muscles display hypertrophy and hyperplasia, with increased Igf2 and decreased myostatin (Mstn) expression. Many imprinted genes are expressed in muscle stem cells or satellite cells. Unexpectedly, the number of satellite cells was reduced by 50% in H19 Δ3 muscle fibers. This reduction occurred after postnatal day 21, suggesting a link with their entry into quiescence. We investigated the biological function of these mutant satellite cells in vivo using a regeneration assay induced by multiple injections of cardiotoxin. Surprisingly, despite their reduced number, the self-renewal capacity of these cells is fully retained in the absence of H19. In addition, we observed a better regeneration potential of the mutant muscles, with enhanced expression of several IGN genes and genes from the IGF pathway.

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“…So it is assumed that DUSP6 should have reverse correlation with VEGFC expression, however, we saw a positive correlation between DUSP6 and VEGFC in our study ( Table 4). Given that there is a complicated negative regulatory feedback loop between ERK1/2 and DUSP6, which also can be transcriptionally regulated by SIX1 (Le Grand et al, 2012) (Figure 1), we thought that the complicity in these important pathways cannot be outlined by single molecule, it is a network that counts.…”

Section: Discussionmentioning

confidence: 99%

“…As a negative regulator of MAKP pathways, DUSP6 can directly inhibit the phosphorylation of ERK1/2 (Maillet et al, 2008;Cejudo-Marin et al, 2012), which can transcriptionally activate DUSP6, that constitutes a feedback regulatory loop between ERK 1/2 and DUSP6 (Furukawa et al, 2008). Intriguingly, SIX1 can also regulate the ERK1/2 pathway by directly controlling DUSP6 transcription (Le Grand et al, 2012). According to previous reports, there are complicated regulatory networks among VEGFC, SIX1, CNTN1 and DUSP6 as summarizing in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Vascular Endothelial Growth Factor-C Related Factors in Stomach Cancer

Liu

Zhao²,

Hu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Six1 regulates stem cell repair potential and self-renewal during skeletal muscle regeneration

Abstract: Six1 in satellite cells is important for muscle regeneration and homeostasis of the stem cell niche by regulating MyoD, Myogenin, and Dusp6-ERK signaling.

Cited by 102 publications

References 41 publications

Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue Repair

Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue Repair

H19 controls reactivation of the imprinted gene network during muscle regeneration

Comprehensive Analysis of Vascular Endothelial Growth Factor-C Related Factors in Stomach Cancer

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