Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2-) macrophages. Herein, we identified an essential role for CCR2- macrophages in the chronically failing heart. Depletion of CCR2- macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2- macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4)-dependent pathway that controlled growth factor expression. These findings establish a role for tissue-resident macrophages in adaptive cardiac remodeling and implicate mechanical sensing in cardiac macrophage activation.
Copyright © 2021 Elsevier Inc. All rights reserved.

h4>ABSTRACT/h4> Collagen XVIII (ColXVIII) is a component of the extracellular matrix implicated in embryogenesis and control of homeostasis. We provide evidence that ColXVIII has a specific role in kidney ontogenesis by regulating the interaction between mesenchymal and epithelial tissues as observed in analyses of total and isoform-specific knockout embryos, mice, and ex vivo organ primordia. ColXVIII deficiency, both temporally and spatially, impacts the 3D pattern of ureteric tree branching morphogenesis via its specific isoforms. Proper development of ureteric tree depends on a tight control of the nephron progenitor cells (NPCs). ColXVIII-deficient NPCs are leaving the NPC pool faster than in controls. Moreover, the data suggests that ColXVIII mediates the kidney epithelial tree patterning via its N-terminal domains, and especially the Thrombospondin-1-like domain, and that this morphogenetic effect involves ureteric epithelial integrins. Altogether, the results propose a significant role for ColXVIII in a complex signalling network regulating renal progenitors and kidney development.

Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.
© 2020 The Authors.

Osteoporosis is the most common degenerative bone disease that occurs when the balance of bone production and resorption is perturbed. Loss of bone mass or alteration in its quality leads to significant weakening of the bones and subsequently to higher fracture risk. Collagen XIII (ColXIII) is a conserved transmembrane protein expressed in many mesenchymal tissues. Here we show that ColXIII is a regulator of bone remodeling niche. In this study, we found that ColXIII expression is significantly upregulated in osteoporotic patients. In view of that, we studied bone homeostasis in ColXIII-overexpressing mice (Col13a1oe) up to 72 weeks of age and observed a cortical bone overgrowth followed by a drastic bone loss, together with increased bone vascularization. Moreover, our results demonstrate that the ColXIII-derived ectodomain enhances angiogenesis through β1-integrins and the JNK pathway. Consequently, these data suggest that ColXIII has a role in age-dependent cortical bone deterioration with possible implications for osteoporosis and fracture risk.
Copyright © 2019 Elsevier B.V. All rights reserved.

We previously established that overexpression of the EGF receptor (EGFR) is sufficient to induce tumor formation by otherwise nontransformed mammary epithelial cells, and that the initiation of epithelial-mesenchymal transition (EMT) is capable of increasing the invasion and metastasis of these cells. Using this breast cancer (BC) model, we find that in addition to EGF, adhesion to fibronectin (FN) activates signal transducer and activator of transcription 3 (STAT3) through EGFR-dependent and -independent mechanisms. Importantly, EMT facilitated a signaling switch from SRC-dependent EGFR:STAT3 signaling in pre-EMT cells to EGFR-independent FN:JAK2:STAT3 signaling in their post-EMT counterparts, thereby sensitizing these cells to JAK2 inhibition. Accordingly, human metastatic BC cells that failed to activate STAT3 downstream of EGFR did display robust STAT3 activity upon adhesion to FN. Furthermore, FN enhanced outgrowth in three-dimensional organotypic cultures via a mechanism that is dependent upon β1 integrin, Janus kinase 2 (JAK2), and STAT3 but not EGFR. Collectively, our data demonstrate that matrix-initiated signaling is sufficient to drive STAT3 activation, a reaction that is facilitated by EMT during BC metastatic progression.