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Cell autonomous ANTXR1-mediated regulation of extracellular matrix components in primary fibroblasts.

ABSTRACT: Our previous studies of Antxr1 knockout mice suggested that fibrotic skin abnormalities in these mice are associated with increased VEGF signaling. Here, based on studies of primary fibroblasts isolated from skin of Antx1+/+ and Antxr1-/- mice at embryonic stage E17.5 and postnatal day P49, we conclude that increased Col1a1 and Fn1 expression in Antxr1-deficient fibroblasts is partly mediated by a cell-autonomous ANTXR1-dependent mechanism. In turn, this may act in parallel with VEGF-dependent regulation of collagen type I and fibronectin production. We demonstrate that shRNA mediated knockdown of VEGF in Antxr1-/- fibroblasts reduces Col1a1 and Fn1 expression to below control levels, and these are restored by exogenous addition of recombinant VEGF. In addition, the increase in protein levels of collagen type I and fibronectin in mutant cells is blocked by VEGF neutralizing antibody. However, expressing the longest isoform of ANTXR1 (sv1) in mutant fibroblasts decreases levels of Ctgf, Col1a1 and Fn1 transcripts, but has no effect on VEGF expression. Taken together, our data suggest that the increased matrix production in Antxr1- deficient fibroblasts primarily occurs via a CTGF-dependent pathway and that other ANTXR1-associated mechanisms contribute to VEGF-dependent increase of collagen type I and fibronectin expression. Our findings provide a basis for further studies of novel ANTXR1-dependent connective tissue homeostatic control mechanisms in healthy individuals, patients with organ fibrosis, and patients with GAPO syndrome.

SUBMITTER: Hu K

PROVIDER: S-EPMC5478475 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Cell autonomous ANTXR1-mediated regulation of extracellular matrix components in primary fibroblasts.

Hu Kai K Olsen Bjorn R BR Besschetnova Tatiana Y TY

Matrix biology : journal of the International Society for Matrix Biology 20161220

Our previous studies of Antxr1 knockout mice suggested that fibrotic skin abnormalities in these mice are associated with increased VEGF signaling. Here, based on studies of primary fibroblasts isolated from skin of Antx1+/+ and Antxr1-/- mice at embryonic stage E17.5 and postnatal day P49, we conclude that increased Col1a1 and Fn1 expression in Antxr1-deficient fibroblasts is partly mediated by a cell-autonomous ANTXR1-dependent mechanism. In turn, this may act in parallel with VEGF-dependent r ...[more]

PMID: 28011198

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Project description:BackgroundCardiac fibroblasts are the main non-myocyte population responsible for extracellular matrix (ECM) production. During perinatal development, fibroblast expansion coincides with the transition from hyperplastic to hypertrophic myocardial growth. Therefore, we investigated the consequences of fibroblast loss at the time of cardiomyocyte maturation by depleting fibroblasts in the perinatal mouse.Methods and resultsWe evaluated the microenvironment of the perinatal heart in the absence of fibroblasts and the potential functional impact of fibroblast loss in regulation of cardiomyocyte cell cycle arrest and binucleation. Cre-mediated expression of diphtheria toxin A in PDGFRα expressing cells immediately after birth eliminated 70-80% of the cardiac fibroblasts. At postnatal day 5, hearts lacking fibroblasts appeared similar to controls with normal morphology and comparable numbers of endothelial and smooth muscle cells, despite a pronounced reduction in fibrillar collagen. Immunoblotting and proteomic analysis of control and fibroblast-deficient hearts identified differential abundance of several ECM proteins. In addition, fibroblast loss decreased tissue stiffness and resulted in increased cardiomyocyte mitotic index, DNA synthesis, and cytokinesis. Moreover, decellularized matrix from fibroblast-deficient hearts promoted cardiomyocyte DNA replication. While cardiac architecture was not overtly affected by fibroblast reduction, few pups survived past postnatal day 11, suggesting an overall requirement for PDGFRα expressing fibroblasts.ConclusionsThese studies demonstrate the key role of fibroblasts in matrix production and cardiomyocyte cross-talk during mouse perinatal heart maturation and revealed that fibroblast-derived ECM may modulate cardiomyocyte maturation in vivo. Neonatal depletion of fibroblasts demonstrated that although hearts can tolerate reduced ECM composition, fibroblast loss eventually leads to perinatal death as the approach simultaneously reduced fibroblast populations in other organs.

Dataset Information

Cell autonomous ANTXR1-mediated regulation of extracellular matrix components in primary fibroblasts.

Publications

Cell autonomous ANTXR1-mediated regulation of extracellular matrix components in primary fibroblasts.

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