Depletion of CD206+ M2-like macrophages induces fibro-adipogenic progenitors activation and muscle regeneration.

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-ß1 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-ß 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.

Astaxanthin, a Marine Carotenoid, Maintains the Tolerance and Integrity of Adipose Tissue and Contributes to Its Healthy Functions.

Recently, obesity-induced insulin resistance, type 2 diabetes, and cardiovascular disease have become major social problems. We have previously shown that Astaxanthin (AX), which is a natural antioxidant, significantly ameliorates obesity-induced glucose intolerance and insulin resistance. It is well known that AX is a strong lipophilic antioxidant and has been shown to be beneficial for acute inflammation. However, the actual effects of AX on chronic inflammation in adipose tissue (AT) remain unclear. To observe the effects of AX on AT functions in obese mice, we fed six-week-old male C57BL/6J on high-fat-diet (HFD) supplemented with or without 0.02% of AX for 24 weeks. We determined the effect of AX at 10 and 24 weeks of HFD with or without AX on various parameters including insulin sensitivity, glucose tolerance, inflammation, and mitochondrial function in AT. We found that AX significantly reduced oxidative stress and macrophage infiltration into AT, as well as maintaining healthy AT function. Furthermore, AX prevented pathological AT remodeling probably caused by hypoxia in AT. Collectively, AX treatment exerted anti-inflammatory effects via its antioxidant activity in AT, maintained the vascular structure of AT and preserved the stem cells and progenitor's niche, and enhanced anti-inflammatory hypoxia induction factor-2α-dominant hypoxic response. Through these mechanisms of action, it prevented the pathological remodeling of AT and maintained its integrity.

Generation and characterization of a Meflin-CreERT2 transgenic line for lineage tracing in white adipose tissue.

Meflin (Islr) expression has gained attention as a marker for mesenchymal stem cells, but its function remains largely unexplored. Here, we report the generation of Meflin-CreERT2 mice with CreERT2 inserted under the Meflin gene promoter to label Meflin-expressing cells genetically, thereby enabling their lineages to be traced. We found that in adult mice, Meflin-expressing lineage cells were present in adipose tissue stroma and had differentiated into mature adipocytes. These cells constituted Crown-like structures in the adipose tissue of mice after high-fat diet loading. Cold stimulation led to the differentiation of Meflin-expressing lineage cells into beige adipocytes. Thus, the Meflin-CreERT2 mouse line is a useful new tool for visualizing and tracking the lineage of Meflin-expressing cells.

Partial depletion of CD206-positive M2-like macrophages induces proliferation of beige progenitors and enhances browning after cold stimulation.

Beige adipocytes are an inducible form of thermogenic adipocytes that become interspersed within white adipose tissue (WAT) depots in response to cold exposure. Previous studies have shown that type 2 cytokines and M2 macrophages induce cold-induced browning in inguinal WAT (ingWAT) by producing catecholamines. Exactly how the conditional and partial depletion of CD206+ M2-like macrophages regulates the cold-induced browning of ingWAT, however, remains unknown. We examined the role of CD206+ M2-like macrophages in the cold-induced browning of WAT using genetically engineered CD206DTR mice, in which CD206+ M2-like macrophages were conditionally depleted. The partial depletion of CD206+ M2-like enhanced UCP1 expression in ingWAT, as shown by immunostaining, and also upregulated the expression of Ucp1 and other browning-related marker genes in ingWAT after cold exposure. A flow cytometry analysis showed that the partial depletion of CD206+ M2-like macrophages caused an increase in the number of beige progenitors in ingWAT in response to cold. Thus, we concluded that CD206+ M2-like macrophages inhibit the proliferation of beige progenitors and that the partial depletion of CD206+ M2-like macrophages releases this inhibition, thereby enhancing browning and insulin sensitivity.