{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T08:45:25Z","timestamp":1790239525511,"version":"4.1.0"},"reference-count":54,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Regulatory, Integrative and Comparative Physiology"],"published-print":{"date-parts":[[2020,1,1]]},"abstract":"<jats:p> Sepsis induces organ dysfunction due to overexpression of the inflammatory host response, resulting in cardiopulmonary and autonomic dysfunction, thus increasing the associated morbidity and mortality. Wharton\u2019s jelly-derived mesenchymal stem cells (WJ-MSCs) express genes and secrete factors with anti-inflammatory properties, neurological and immunological protection, as well as improve survival in experimental sepsis. The cholinergic anti-inflammatory pathway (CAP) is mediated by \u03b17-nicotinic acetylcholine receptors (\u03b17nAChRs), which play an important role in the control of systemic inflammation. We hypothesized that WJ-MSCs attenuate sepsis-induced organ injury in the presence of an activated CAP pathway. To confirm our hypothesis, we evaluated the effects of WJ-MSCs as a treatment for cardiopulmonary injury and on neuroimmunomodulation. Male Wistar rats were randomly divided into four groups: control (sham-operated); cecal ligation and puncture (CLP) alone; CLP+WJ-MSCs (1\u2009\u00d7\u200910<jats:sup>6<\/jats:sup> cells, at 6 h post-CLP); and CLP+methyllycaconitine (MLA)+WJ-MSCs (5 mg\/kg body wt, at 5.5 h post-CLP, and 1\u2009\u00d7\u200910<jats:sup>6<\/jats:sup> cells, at 6 h post-CLP, respectively). All experiments, including the assessment of echocardiographic parameters and heart rate variability, were performed 24 h after CLP. WJ-MSC treatment attenuated diastolic dysfunction and restored baroreflex sensitivity. WJ-MSCs also increased cardiac sympathetic and cardiovagal activity. WJ-MSCs reduced leukocyte infiltration and proinflammatory cytokines, effects that were abolished by administration of a selective \u03b17nAChR antagonist (MLA). In addition, WJ-MSC treatment also diminished apoptosis in the lungs and spleen. In cardiac and splenic tissue, WJ-MSCs downregulated \u03b17nAChR expression, as well as reduced the phospho-STAT3-to-total STAT3 ratio in the spleen. WJ-MSCs appear to protect against sepsis-induced organ injury by reducing systemic inflammation, at least in part, via a mechanism that is dependent on an activated CAP. <\/jats:p>","DOI":"10.1152\/ajpregu.00098.2018","type":"journal-article","created":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T09:00:51Z","timestamp":1570611651000},"page":"R135-R147","source":"Crossref","is-referenced-by-count":28,"title":["Wharton\u2019s jelly-derived mesenchymal stem cells attenuate sepsis-induced organ injury partially via cholinergic anti-inflammatory pathway activation"],"prefix":"10.1152","volume":"318","author":[{"given":"Jos\u00e9 Manuel C\u00f3ndor","family":"Capcha","sequence":"first","affiliation":[{"name":"Laboratory of Genetics, Cellular Biology, and Molecular Biology, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"},{"name":"Laboratory of Basic Research, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila Eleut\u00e9rio","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Laboratory of Basic Research, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7496-9178","authenticated-orcid":false,"given":"Roberto de Souza","family":"Moreira","sequence":"additional","affiliation":[{"name":"Laboratory of Basic Research, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"},{"name":"Federal University of Goi\u00e1s at Catal\u00e3o, Catal\u00e3o, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo Duarte","family":"Silveira","sequence":"additional","affiliation":[{"name":"Laboratory of Basic Research, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo","family":"Dourado","sequence":"additional","affiliation":[{"name":"Heart Institute, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Heart Institute, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Claudia","family":"Irigoyen","sequence":"additional","affiliation":[{"name":"Heart Institute, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Jensen","sequence":"additional","affiliation":[{"name":"Heart Institute, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margoth Ramos","family":"Garnica","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Cellular Biology, and Molecular Biology, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene L","family":"Noronha","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Cellular Biology, and Molecular Biology, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00facia","family":"Andrade","sequence":"additional","affiliation":[{"name":"Laboratory of Basic Research, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samirah Abreu","family":"Gomes","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Cellular Biology, and Molecular Biology, University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/01.CCM.0000282072.56245.91"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/aas.12472"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.10056"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2014.01.006"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjsurg.2015.06.002"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-010-9204-5"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035361"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.5966\/sctm.2015-0138"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-199607000-00008"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nri3552"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms140917986"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/sctm.16-0415"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ni1229"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehq244"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.2174\/157488811794480762"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000001882"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit669"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-200107000-00013"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e31821c2330"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00180.2011"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000000107"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2015.08.008"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-010-9228-x"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00518.2010"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2013.12.007"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.601005"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.2009.05327.x"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.17226\/12910"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(97)00144-7"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.08.007"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2007.10.006"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-015-8718-1"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201040540"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcrc.2003.08.005"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1067\/mje.2002.120202"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-017-0475-8"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0803237105"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.echo.2010.05.010"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3949\/ccjm.78.s1.04"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.58.6.1072"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1097\/01.CCM.0000178181.91250.99"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1097\/00075198-200110000-00002"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-014-9954-6"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2011.0722"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901808"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(02)02820-6"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/nature01321"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1186\/s13643-015-0103-6"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.beha.2011.01.004"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/nature01339"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2010.03.010"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1006\/jsre.1996.0214"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2006.03169.x"}],"container-title":["American Journal of Physiology-Regulatory, Integrative and Comparative Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpregu.00098.2018","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T20:28:37Z","timestamp":1577737717000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpregu.00098.2018"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,1]]},"references-count":54,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1,1]]}},"alternative-id":["10.1152\/ajpregu.00098.2018"],"URL":"https:\/\/doi.org\/10.1152\/ajpregu.00098.2018","relation":{},"ISSN":["0363-6119","1522-1490"],"issn-type":[{"value":"0363-6119","type":"print"},{"value":"1522-1490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,1]]}}}