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      Human Adipose-Derived Stem Cells Suppress Elastase-Induced Murine Abdominal Aortic Inflammation and Aneurysm Expansion through Paracrine Factors

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          Abstract

          Abdominal aortic aneurysm (AAA) is a potentially lethal disease associated with immune activation-induced aortic degradation. We hypothesized that xenotransplantation of human adipose-derived stem cells (hADSCs) would reduce aortic inflammation and attenuate expansion in a murine AAA model. Modulatory effects of ADSCs on immune cell subtypes associated with AAA progression were investigated using human peripheral blood mononuclear cells (hPBMNCs) cocultured with ADSCs. Murine AAA was induced through elastase application to the abdominal aorta in C57BL/6 mice. ADSCs were administered intravenously, and aortic changes were determined by ultrasonography and videomicrometry. Circulating monocytes, aortic neutrophils, CD28 T cells, FoxP3 + regulatory T cells (Tregs), and CD206 + M2 macrophages were assessed at multiple terminal time points. In vitro, ADSCs induced M2 macrophage and Treg phenotypes while inhibiting neutrophil transmigration and lymphocyte activation without cellular contact. Intravenous ADSC delivery reduced aneurysmal expansion starting from day 4 [from baseline: 54.8% (saline) vs. 16.9% (ADSCs), n = 10 at baseline, n = 4 at day 4, p < 0.001], and the therapeutic effect persists through day 14 (from baseline: 64.1% saline vs. 24.6% ADSCs, n = 4, p < 0.01). ADSC administration increased aortic Tregs by 20-fold ( n = 5, p < 0.01), while decreasing CD4 +CD28 (-28%), CD8 +CD28 T cells (-61%), and Ly6G/C + neutrophils (-43%, n = 5, p < 0.05). Circulating CD115 +CXCR1 LY6C +-activated monocytes decreased in the ADSC-treated group by day 7 (-60%, n = 10, p < 0.05), paralleled by an increase in aortic CD206 + M2 macrophages by 2.4-fold ( n = 5, p < 0.05). Intravenously injected ADSCs transiently engrafted in the lung on day 1 without aortic engraftment at any time point. In conclusion, ADSCs exhibit pleiotropic immunomodulatory effects in vitro as well as in vivo during the development of AAA. The temporal evolution of these effects systemically as well as in aortic tissue suggests that ADSCs induce a sequence of anti-inflammatory cellular events mediated by paracrine factors, which leads to amelioration of AAA progression.

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          Author and article information

          Journal
          Cell Transplant
          Cell Transplant
          CLL
          spcll
          Cell Transplantation
          SAGE Publications (Sage CA: Los Angeles, CA )
          0963-6897
          1555-3892
          1 February 2017
          February 2017
          : 26
          : 2
          : 173-189
          Affiliations
          []Indiana Center for Vascular Biology and Medicine (ICVBM), Indianapolis, IN, USA
          []Richard L. Roudebush VA Center for Regenerative Medicine, Indianapolis, IN, USA
          []Indiana University Department of Surgery (IUSM), Indianapolis, IN, USA
          [§ ]Indiana University Center for Aortic Disease (IU-CAD), Indianapolis, IN, USA
          []Krannert Institute of Cardiology, Indianapolis, IN, USA
          Author notes
          [*]Richard L. Roudebush VA Medical Center, 1481 W 10th Street, C3113, Indianapolis, IN 46202, USA. Tel: (317) 988-4976; Fax: (317) 988-9325; E-mail: jiexie@ 123456iupui.edu
          Article
          PMC5657756 PMC5657756 5657756 10.3727_096368916X692212
          10.3727/096368916X692212
          5657756
          27436185
          107f554f-b7a2-415f-9e30-0c290e1f1ceb
          © 2017 Cognizant, LLC.
          History
          : 27 January 2016
          : 13 September 2016
          Categories
          Article

          Abdominal aortic aneurysm (AAA),M2 macrophage,Regulatory T cells (Tregs),Adipose-derived stem cells (ADSCs),Paracrine signaling

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