ldn-193189 and Fibrosis

Hair follicle dermal sheath (DS) harbors hair follicle dermal stem cells (hfDSCs), which can be recruited to replenish DS and dermal papilla (DP). Cultured DS cells can differentiate into various cell lineages in vitro. However, it is unclear how its plasticity is modulated in vivo. Wnt/β-catenin signaling plays an important role in maintaining stem cells of various lineages and is required for HF development and regeneration. Here we report that activation of β-catenin in DS generates ectopic HF outgrowth (EF) by reprogramming HF epidermal cells and DS cells themselves, and endows DS cells with hair inducing ability. Epidermal homeostasis of pre-existing HFs is disrupted. Additionally, cell-autonomous progressive skin fibrosis is prominent in dermis, where the excessive fibroblasts largely originate from DS. Gene expression analysis of purified DS cells with activated β-catenin revealed significantly increased expression of Bmp, Fgf, and Notch ligands and administration of Bmp, Fgf, or Notch signaling inhibitor attenuates EF formation. In summary, our findings advance the current knowledge of high plasticity of DS cells and provide an insight into understanding how Wnt/β-catenin signaling controls DS cell behaviors.

Topics: Animals; beta Catenin; Bone Morphogenetic Proteins; Cell Proliferation; Cellular Reprogramming; Fibroblast Growth Factors; Fibrosis; Gene Expression Regulation; Hair; Hair Follicle; Mice; Mice, Transgenic; Phenylurea Compounds; Pyrazoles; Pyrimidines; Receptors, Notch; Skin; Smad Proteins; Stem Cells; Wnt Signaling Pathway

Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis.

Topics: Activin Receptors, Type I; Activin Receptors, Type II; Angiotensin II; Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type I; Cardiomegaly; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrosis; Inhibitor of Differentiation Protein 1; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; NFATC Transcription Factors; Phenylephrine; Phosphorylation; Pyrazoles; Pyrimidines; Rats, Sprague-Dawley; RNA Interference; Signal Transduction; Smad Proteins; Time Factors; Transfection