{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T14:46:41Z","timestamp":1766587601040},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"vor","delay-in-days":1613,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Transplantation of adult stem cells into myocardial tissue after acute myocardial infarction (AMI), has been shown to improve tissue recovery and prevent progression to ischemic cardiomyopathy. Studies suggest that the effects of mesenchymal stem cells (MSC) are due to paracrine factors released by MSC, as the benefits of MSC can be achieved through delivery of conditioned media (CM) alone. We previously demonstrated that downregulation of Dab2 enhances MSC cardiac protein expression and improves cardiac function after AMI following MSC engraftment. In order to define the molecular mechanisms that regulate MSC secretome, we analyzed gene arrays in MSC following downregulation of Dab2 via TGF\u03b21 pretreatment or transfection with Dab2:siRNA or miR-145. We identified 23 genes whose expressions were significantly changed in all three conditions. Among these genes, we have initially focused our validation and functional work on calcium\/calmodulin-dependent protein kinase kinase-1 (CAMKK1). We quantified the effects of CAMKK1 overexpression in MSC following injection of CM after AMI. Injections of CM from MSC with CAMKK1 over-expression correlated with an increase in vascular density (CAMKK1 CM: 2,794.95\u2009\u00b1\u200944.2 versus Control: 1,290.69\u2009\u00b1\u20092.8 vessels\/mm2) and decreased scar formation (CAMKK1 CM 50%\u2009\u00b1\u20093.2% versus Control: 28%\u2009\u00b1\u20091.4%), as well as improved cardiac function. Direct overexpression of CAMKK1 in infarcted tissue using a CAMKK1-encoding plasmid significantly improved ejection fraction (CAMKK1: 83.2%\u2009\u00b1\u20095.4% versus saline: 51.7%\u2009\u00b1\u20095.8%. Baseline: 91.3%\u2009\u00b1\u20094.3%) and decreased infarct size after AMI. Our data identify a novel role for CAMKK1 as regulator of the MSC secretome and demonstrate that direct overexpression of CAMKK1 in infarcted cardiac tissue, results in therapeutic beneficial effects.<\/jats:p>","DOI":"10.1002\/sctm.17-0046","type":"journal-article","created":{"date-parts":[[2017,7,8]],"date-time":"2017-07-08T09:26:37Z","timestamp":1499505997000},"page":"1759-1766","source":"Crossref","is-referenced-by-count":15,"title":["A Novel Role for CAMKK1 in the Regulation of the Mesenchymal Stem Cell Secretome"],"prefix":"10.1093","volume":"6","author":[{"given":"Feng","family":"Dong","sequence":"first","affiliation":[{"name":"a Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shyam","family":"Patnaik","sequence":"additional","affiliation":[{"name":"a Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong-Hui","family":"Duan","sequence":"additional","affiliation":[{"name":"b Computer Science, University of Akron, Akron, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Kiedrowski","sequence":"additional","affiliation":[{"name":"a Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc S.","family":"Penn","sequence":"additional","affiliation":[{"name":"a Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA"},{"name":"c Cardiovascular Department, Summa Cardiovascular Institute, Summa Health System, Akron, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maritza E.","family":"Mayorga","sequence":"additional","affiliation":[{"name":"a Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2017,7,8]]},"reference":[{"key":"2022022809341264400_R1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11886-015-0693-6","article-title":"Current state of stem cell therapy for ischemic heart disease","volume":"18","author":"Povsic","year":"2016","journal-title":"Curr Cardiol Rep"},{"key":"2022022809341264400_R2","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s12265-014-9580-6","article-title":"Endomyocardial implantation of autologous bone marrow mononuclear cells in advanced ischemic heart failure: A randomized placebo-controlled trial (END-HF)","volume":"7","author":"Santoso","year":"2014","journal-title":"J Cardiovasc Transl Res"},{"key":"2022022809341264400_R3","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1161\/CIRCRESAHA.115.306838","article-title":"Cardiac stem cell hybrids enhance myocardial repair","volume":"117","author":"Quijada","year":"2015","journal-title":"Circ Res"},{"key":"2022022809341264400_R4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2217\/rme.09.74","article-title":"Stem cell paracrine actions and tissue regeneration","volume":"5","author":"Baraniak","year":"2010","journal-title":"Regen Med"},{"key":"2022022809341264400_R5","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.stem.2012.02.005","article-title":"Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease","volume":"10","author":"Ranganath","year":"2012","journal-title":"Cell Stem Cell"},{"key":"2022022809341264400_R6","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.it.2011.11.004","article-title":"How mesenchymal stem cells interact with tissue immune responses","volume":"33","author":"Shi","year":"2012","journal-title":"Trends Immunol"},{"key":"2022022809341264400_R7","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1161\/CIRCULATIONAHA.111.082453","article-title":"Myocardial CXCR4 expression is required for mesenchymal stem cell mediated repair following acute myocardial infarction","volume":"126","author":"Dong","year":"2012","journal-title":"Circulation"},{"key":"2022022809341264400_R8","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1096\/fj.06-6558com","article-title":"SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction","volume":"21","author":"Zhang","year":"2007","journal-title":"FASEB J"},{"key":"2022022809341264400_R9","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1089\/scd.2010.0151","article-title":"Central role for disabled-2 in mesenchymal stem cardiac protein expression and functional consequences after engraftment in acute myocardial infarction. 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