title: Inhibition of Wnt6 by Sfrp2 regulates adult cardiac progenitor cell differentiation by differential modulation of Wnt pathways.
abstract: Wnt signaling has recently emerged as an important regulator of cardiac progenitor cell proliferation and differentiation, but the exact mechanisms by which Wnt signaling modulates these effects are not known. Understanding these mechanisms is essential for advancing our knowledge of cardiac progenitor cell biology and applying this knowledge to enhance cardiac therapy. Here, we explored the effects of Sfrp2, a canonical Wnt inhibitor, in adult cardiac progenitor cell (CPC) differentiation and investigated the molecular mechanisms involved. Our data show that Sfrp2 treatment can promote differentiation of CPCs after ischemia-reperfusion injury. Treatment of CPCs with Sfrp2 inhibited CPC proliferation and primed them for cardiac differentiation. Sfrp2 binding to Wnt6 and inhibition of Wnt6 canonical pathway was essential for the inhibition of CPC proliferation. This inhibition of Wnt6 canonical signaling by Sfrp2 was important for activation of the non-canonical Wnt/Planar Cell Polarity (PCP) pathway through JNK, which in turn induced expression of cardiac transcription factors and CPC differentiation. Taken together, these results demonstrate a novel role of Sfrp2 and Wnt6 in regulating the dynamic process of CPC proliferation and differentiation, as well as providing new insights into the mechanisms of Wnt signaling in cardiac differentiation.
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schmeckpeper
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Verma
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Yin
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA.
authors.forename: Farideh
authors.initials: F
authors.lastname: Beigi
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA.
authors.forename: Lunan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Payne
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA; Duke Cardiovascular Research Center, Durham, NC 27710, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pratt
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA; Duke Cardiovascular Research Center, Durham, NC 27710, USA. Electronic address: victor.dzau@duke.edu.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA; Duke Cardiovascular Research Center, Durham, NC 27710, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Mirotsou
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D015870:Gene Expression; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C095936:Wnt6 protein, mouse
keywords: Cardiac injury; Cardiac progenitor cells; Differentiation; Sfrp2; Wnt signaling