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Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment\u2010dependent changes in inflammatory monocytes after MI. RNA sequencing analysis of murine Ly6C\n                    <jats:sup>high<\/jats:sup>\n                    monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade. Analysis of WNT modulators revealed a strong upregulation of WNT Inhibitory Factor 1 (WIF1) in cardiomyocytes\u2014but not fibroblasts or endothelial cells\u2014upon hypoxia. Compared to wild\u2010type (WT) littermates, WIF1 knockout mice showed severe adverse remodeling marked by increased scar size and reduced ejection fraction 4\u00a0weeks after MI. While FACS analysis on day 1 after MI revealed no differences in neutrophil numbers, the hearts of WIF1 knockouts contained significantly more inflammatory monocytes than hearts from WT animals. Next, we induced AAV\u2010mediated cardiomyocyte\u2010specific WIF1 overexpression, which attenuated the\u00a0monocyte response and improved cardiac function after MI, as\u00a0compared to control\u2010AAV\u2010treated animals. Finally, WIF1 overexpression in isolated cardiomyocytes limited the activation of non\u2010canonical WNT signaling and led to reduced IL\u20101\u03b2 and IL\u20106 expression in monocytes\/macrophages. Taken together, we investigated the cardiac microenvironment's interaction with recruited monocytes after MI and identified a novel mechanism of monocyte activation. The local initiation of non\u2010canonical WNT signaling shifts the accumulating myeloid cells toward a pro\u2010inflammatory state and impacts healing after myocardial infarction.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201707565","type":"journal-article","created":{"date-parts":[[2017,8,3]],"date-time":"2017-08-03T20:20:14Z","timestamp":1501791614000},"page":"1279-1293","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["The cardiac microenvironment uses non\u2010canonical WNT signaling to activate monocytes after myocardial infarction"],"prefix":"10.1038","volume":"9","author":[{"given":"Ingmar S\u00f6ren","family":"Meyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Jungmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Dieterich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Lasitschka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susann","family":"Werkmeister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Haas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver J","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Boutros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Nahrendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo A","family":"Katus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan E","family":"Hardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1157-474X","authenticated-orcid":false,"given":"Florian","family":"Leuschner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,3]]},"reference":[{"key":"BFEMMM201707565_CR1","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1093\/eurheartj\/ehr388","volume":"33","author":"B Assmus","year":"2012","unstructured":"Assmus B, Iwasaki M, Sch\u00e4chinger V, Roexe T, Koyanagi M, Lekushi K, Xu Q, Tonn T, Seifried E, Liebner S et\u00a0al (2012) Acute myocardial infarction activates progenitor cells and increase Wnt signalling in the bone marrow. 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