{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T10:54:06Z","timestamp":1788778446299,"version":"build-2803163510"},"reference-count":84,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:00:00Z","timestamp":1717372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Mercer University School of Medicine\u2019s Research funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mesenchymal stromal cells (MSCs) are investigated as cellular therapeutics for inflammatory bowel diseases and associated perianal fistula, although consistent efficacy remains a concern. Determining host factors that modulate MSCs\u2019 potency including their secretion of angiogenic and wound-healing factors, immunosuppression, and anti-inflammatory properties are important determinants of their functionality. We investigated the mechanisms that regulate the secretion of angiogenic and wound-healing factors and immune suppression of human bone marrow MSCs. Secretory analysis of MSCs focusing on 18 angiogenic and wound-healing secretory molecules identified the most abundancy of vascular endothelial growth factor A (VEGF-A). MSC viability and secretion of other angiogenic factors are not dependent on VEGF-A secretion which exclude the autocrine role of VEGF-A on MSC\u2019s fitness. However, the combination of inflammatory cytokines IFN\u03b3 and TNF\u03b1 reduces MSC\u2019s VEGF-A secretion. To identify the effect of intestinal microvasculature on MSCs\u2019 potency, coculture analysis was performed between human large intestine microvascular endothelial cells (HLMVECs) and human bone marrow-derived MSCs. HLMVECs do not attenuate MSCs\u2019 viability despite blocking their VEGF-A secretion. In addition, HLMVECs neither attenuate MSC\u2019s IFN\u03b3 mediated upregulation of immunosuppressive enzyme indoleamine 2,3-dioxygenase nor abrogate suppression of T-cell proliferation despite the attenuation of VEGF-A secretion. We found that HLMVECs express copious amounts of endothelial nitric oxide synthase and mechanistic analysis showed that pharmacological blocking reverses HLMVEC-mediated attenuation of MSC\u2019s VEGF-A secretion. Together these results suggest that secretion of VEGF-A and immunosuppression are separable functions of MSCs which are regulated by distinct mechanisms in the host.<\/jats:p>","DOI":"10.1093\/stmcls\/sxae040","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T14:23:13Z","timestamp":1717424593000},"page":"736-751","source":"Crossref","is-referenced-by-count":16,"title":["Vascular endothelial growth factor secretion and immunosuppression are distinct potency mechanisms of human bone marrow mesenchymal stromal cells"],"prefix":"10.1093","volume":"42","author":[{"given":"Tyler U","family":"Faircloth","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine , Savannah, GA 31324, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Temple","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine , Savannah, GA 31324, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhett N","family":"Parr","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine , Savannah, GA 31324, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna B","family":"Tucker","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine , Savannah, GA 31324, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devi","family":"Rajan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine , Savannah, GA 31324, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiman","family":"Hematti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical College of Wisconsin , Milwaukee, WI 53226, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8686-4189","authenticated-orcid":false,"given":"Subra","family":"Kugathasan","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine and Children\u2019s Healthcare of Atlanta , Atlanta, GA, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1877-8975","authenticated-orcid":false,"given":"Raghavan","family":"Chinnadurai","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine , Savannah, GA 31324, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"issue":"10051","key":"2024080104504579900_CIT0001","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/S0140-6736(16)31203-X","article-title":"Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn\u2019s disease: a phase 3 randomised, double-blind controlled trial","volume":"388","author":"Panes","year":"2016","journal-title":"Lancet"},{"issue":"1","key":"2024080104504579900_CIT0002","doi-asserted-by":"crossref","first-page":"41","DOI":"10.2174\/1381612825666190308095651","article-title":"Cell-based therapy for perianal Fistulising Crohn\u2019s disease","volume":"25","author":"Kotze","year":"2019","journal-title":"Curr Pharm Des"},{"issue":"5","key":"2024080104504579900_CIT0003","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1093\/ibd\/izz215","article-title":"Matrix-delivered autologous mesenchymal stem cell therapy for refractory rectovaginal Crohn\u2019s Fistulas","volume":"26","author":"Lightner","year":"2020","journal-title":"Inflamm Bowel Dis"},{"issue":"6","key":"2024080104504579900_CIT0004","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1136\/gut.2010.214841","article-title":"Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn\u2019s disease","volume":"60","author":"Ciccocioppo","year":"2011","journal-title":"Gut"},{"issue":"2","key":"2024080104504579900_CIT0005","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/bph.15305","article-title":"Developing cell therapies as drug products","volume":"178","author":"Ciccocioppo","year":"2021","journal-title":"Br J Pharmacol"},{"issue":"5","key":"2024080104504579900_CIT0006","doi-asserted-by":"crossref","first-page":"532","DOI":"10.5966\/sctm.2014-0199","article-title":"Long-term results of adipose-derived stem cell therapy for the treatment of Crohn\u2019s fistula","volume":"4","author":"Cho","year":"2015","journal-title":"Stem Cells Transl. 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