Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction (MI) and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell type in terms of their origins and functional effects in vivo. Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen-inducible Cre for cellular lineage-tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Lineage tracing with four additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after MI. Periostin-traced myofibroblasts also revert back to a less-activated state upon injury resolution. Our results define the myofibroblast as a periostin-expressing cell type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts.

SUMMARY The purposes of this study were to determine whether 1) cerebral vessels undergo hypertrophy during chronic hypertension and 2) sympathetic nenes contribute to cerebral vascular changes In chronic hypertension. Morphometiic studies were undertaken in stroke-prone spontaneously hypertensive rats (SP-SHR) and normotenslve Wistar-Kyoto (WKY) rats. Unilateral superior cerrical gangUonectomy was performed in the SP-SHR at 8 weeks of age. When the rats were approximately 13 months old, they were killed and the brain was fixed with formalin at a perfusion pressure of 80% of the rat's systolic pressure. Wall/lumen ratio was measured in approximately 1200 arteries and arterioles. In parenchymal, but not pial, cerebral vessels there was pronounced vascular hypertrophy in SP-SHR: wall/lumen ratio was 0.08 in WKY and 0.14 in SP-SHR (p < 0.05). Sympathetic denervation attenuated the development of vascular hypertrophy in SP-SHR: wall/lumen ratio was 0.14 in the innervated parenchymal vessels, and 0.10 in denervated vessels (p < 0.05). We conclude that cerebral vessels undergo hypertrophy in stroke-prone SHR and speculate that vascular hypertrophy may protect cerebral vessels by reducing wall stress in chronic hypertension. Sympathetic nerves appear to exert a trophic effect on cerebral vascular muscle in chronic hypertension. 1 have emphasized the concept that an increase in wall/lumen ratio may be an important factor in the pathogenesis and maintenance of hypertension. Vascular hypertrophy appears to be of physiologic importance both in limiting blood flow during maximal vasodilatation and in increasing vascular responsiveness to constrictor stimuli. Vascular hypertrophy, however, also may serve a protective function, by attenuating increases in capillary pressure during hypertension.1 This protective effect could be especially important in cerebral vessels in which sudden increases in arterial pressure produce disruption of the blood-brain barrier. 419vessels in most other organs, would undergo hypertrophy during chronic hypertension. On the other hand, large arteries that supply the brain appear to contribute importantly to cerebral vascular resistance 11 -u and to minimize increases in pressure in distal vessels during acute hypertension." Thus, if small cerebral arteries are protected from increases in pressure by increases in resistance in upstream vessels, small cerebral arteries might not undergo hypertrophy during chronic hypertension.The first goal of this study was to determine whether cerebral arteries and arterioles undergo hypertrophy during chronic hypertension. Specifically, we determined wall/lumen ratio in cerebral vessels of stroke-prone SHR and normotensive Wistar-Kyoto (WKY) rats.Our second goal was to determine whether sympathetic nerves contribute to cerebral vascular changes in chronic hypertension. Bevan 1 * and Bevan and Tsuru 14 have proposed that sympathetic nerves exert a "trophic" effect and contribute to the normal development of arteries. Thus, sympathetic nerves also might contribute...

Leucine-rich repeat containing 10 (LRRC10) is a cardiac-specific protein exclusively expressed in embryonic and adult cardiomyocytes. However, the role of LRRC10 in mammalian cardiac physiology remains unknown. To determine if LRRC10 is critical for cardiac function, Lrrc10-null (Lrrc10−/−) mice were analyzed. Lrrc10− /− mice exhibit prenatal systolic dysfunction and dilated cardiomyopathy in postnatal life. Importantly, Lrrc10−/− mice have diminished cardiac performance in utero, prior to ventricular dilation observed in young adults. We demonstrate that LRRC10 endogenously interacts with α-actinin and α-actin in the heart and all actin isoforms in vitro. Gene expression profiling of embryonic Lrrc10−/− hearts identified pathways and transcripts involved in regulation of the actin cytoskeleton to be significantly upregulated, implicating dysregulation of the actin cytoskeleton as an early defective molecular signal in the absence of LRRC10. In contrast, microarray analyses of adult Lrrc10−/− hearts identified upregulation of oxidative phosphorylation and cardiac muscle contraction pathways during the progression of dilated cardiomyopathy. Analyses of hypertrophic signal transduction pathways indicate increased active forms of Akt and PKCε in adult Lrrc10−/− hearts. Taken together, our data demonstrate that LRRC10 is essential for proper mammalian cardiac function. We identify Lrrc10 as a novel dilated cardiomyopathy candidate gene and the Lrrc10−/− mouse model as a unique system to investigate pediatric cardiomyopathy.

Skeletal muscle is highly sensitive to mutations in genes that participate in membrane stability and cellular attachment, which often leads to muscular dystrophy. Here we show that Thrombospondin-4 (Thbs4) regulates skeletal muscle integrity and its susceptibility to muscular dystrophy through organization of membrane attachment complexes. Loss of the Thbs4 gene causes spontaneous dystrophic changes with aging and accelerates disease in 2 mouse models of muscular dystrophy, while overexpression of mouse Thbs4 is protective and mitigates dystrophic disease. In the myofiber, Thbs4 selectively enhances vesicular trafficking of dystrophin-glycoprotein and integrin attachment complexes to stabilize the sarcolemma. In agreement, muscle-specific overexpression of Drosophila Tsp or mouse Thbs4 rescues a Drosophila model of muscular dystrophy with augmented membrane residence of βPS integrin. This functional conservation emphasizes the fundamental importance of Thbs’ as regulators of cellular attachment and membrane stability and identifies Thbs4 as a potential therapeutic target for muscular dystrophy.DOI: http://dx.doi.org/10.7554/eLife.17589.001