Human adipose-derived stem cells suppress elastase-induced murine abdominal aortic inflammation and aneurysm expansion through paracrine factors

Jie Xie, Thomas J. Jones, Dongni Feng, Todd G. Cook, Andrea A. Jester, Ru Yi, Yameena T. Jawed, Clifford Babbey, Keith L. March, Michael Murphy

Research output: Contribution to journalArticle

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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+CXCR1LY6C+-activated monocytes decreased in the ADSC-treated group by day 7 (−60%, n = 10, p V< 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 immunemodulatory 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.

Original languageEnglish (US)
Pages (from-to)173-189
Number of pages17
JournalCell Transplantation
Volume26
Issue number2
DOIs
StatePublished - 2017

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T-cells
Macrophages
Pancreatic Elastase
Abdominal Aortic Aneurysm
Stem cells
Stem Cells
Inflammation
Chemical activation
Ultrasonography
Lymphocytes
Monocytes
Neutrophils
Blood
Tissue
T-Lymphocytes
Degradation
Neutrophil Activation
Heterologous Transplantation
Abdominal Aorta
Therapeutic Uses

Keywords

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

ASJC Scopus subject areas

  • Biomedical Engineering
  • Cell Biology
  • Transplantation

Cite this

Human adipose-derived stem cells suppress elastase-induced murine abdominal aortic inflammation and aneurysm expansion through paracrine factors. / Xie, Jie; Jones, Thomas J.; Feng, Dongni; Cook, Todd G.; Jester, Andrea A.; Yi, Ru; Jawed, Yameena T.; Babbey, Clifford; March, Keith L.; Murphy, Michael.

In: Cell Transplantation, Vol. 26, No. 2, 2017, p. 173-189.

Research output: Contribution to journalArticle

Xie, Jie ; Jones, Thomas J. ; Feng, Dongni ; Cook, Todd G. ; Jester, Andrea A. ; Yi, Ru ; Jawed, Yameena T. ; Babbey, Clifford ; March, Keith L. ; Murphy, Michael. / Human adipose-derived stem cells suppress elastase-induced murine abdominal aortic inflammation and aneurysm expansion through paracrine factors. In: Cell Transplantation. 2017 ; Vol. 26, No. 2. pp. 173-189.
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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 V< 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 immunemodulatory 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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AU - Jones, Thomas J.

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AU - Jester, Andrea A.

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AU - Jawed, Yameena T.

AU - Babbey, Clifford

AU - March, Keith L.

AU - Murphy, Michael

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