Browsing by Author "Xie, Jie"

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    HUMAN ADIPOSE-DERIVED STEM CELLS ATTENUATE CIGARETTE SMOKE INDUCED BONE MARROW HYPOPLASIA VIA SECRETION OF ANTI-INFLAMMATORY CYTOKINE TSG-6
    (Office of the Vice Chancellor for Research, 2012-04-13) Xie, Jie; Petrache, Irina; Broxmeyer, Hal E.; March, Keith L.; Feng, Dongni; Cook, Todd G.; Schweitzer, Kelly; Johnstone, Brian H.
    Introduction We have previously observed bone marrow (BM) hypo-plasia in a murine model of chronic smoking, which was ameliorated by mu-rine adipose-derived stromal cells (ASC). This study was designed to test the hypothesis that ASC exert their marrow protective effects through key paracrine factors. Methods Mice (NSG or C57BL/6) were exposed to ciga-rette smoke (CS) for 1 day to 6 months. Human ASC or ASC conditioned media were administered through intravenous (i.v.) or intraperitoneal (i.p.) injections. Secretion of TSG-6 from ASC in response to TNF alpha and IL-1 beta were measured by ELISA. Expression of TSG-6 in ASC was knocked down by siRNA. BM hematopoietic progenitors were quantified by colony forming-unit assays. Possible engrafted human ASC in mouse BM were ex-amined by anti-human nuclei staining. Results The myelossupressive effect of cigarette smoking occurred acutely (1 day: 65.6% of nonsmoking control, NSC, p<0.01) and worsened with prolonged exposure (3 days: 34.3% NSC, p<0.01). Such damage could be ameliorated with either ASC (111.0% NSC, p>0.05) or ASC conditioned media (105.7% NSC, p>0.05). Inflammatory cytokines (TNF alpha and IL-1 beta) elevated in smokers (Kuschner et al, 1996; de Maat et al, 2002) demonstrated strong cross-species stimulatory effects on secretions of an anti-inflammatory cytokine, TSG-6 from ASC (TNF alpha: 8.7 +/- 1.3 fold, IL-1 beta: 8.2 +/- 1.1 fold). Knocking down TSG-6 (>90%) abolished the marrow-protective effect of ASC. No human cells were detected in recipient mouse bone marrow. Conclusions The pro-tective effects of ASC against smoking-induced myelosuppression are medi-ated by trophic factors rather than cell engraftment or differentiation. TSG-6 appears to play a significant role in the modulatory pathway: smoke--inflammatory cytokine release--TSG6 secretion from ASC--bone marrow protection.
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    Human Adipose-Derived Stem Cells Suppress Elastase-Induced Murine Abdominal Aortic Inflammation and Aneurysm Expansion Through Paracrine Factors
    (Sage, 2017-02) 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 P.; Department of Anesthesia, School of Medicine
    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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    Intravenous xenogeneic transplantation of human adipose-derived stem cells improves left ventricular function and microvascular integrity in swine myocardial infarction model
    (Wiley, 2015-08) Hong, Soon Jun; Rogers, Pamela I.; Kihlken, John; Warfel, Jessica; Bull, Chris; Deuter-Reinhard, Maja; Feng, Dongni; Xie, Jie; Kyle, Aaron; Merfeld-Clauss, Stephanie; Johnstone, Brian H.; Traktuev, Dmitry O.; Chen, Peng-Sheng; Lindner, Jonathan R.; March, Keith L.; Medicine, School of Medicine
    OBJECTIVES: The potential for beneficial effects of adipose-derived stem cells (ASCs) on myocardial perfusion and left ventricular dysfunction in myocardial ischemia (MI) has not been tested following intravenous delivery. METHODS: Surviving pigs following induction of MI were randomly assigned to 1 of 3 different groups: the placebo group (n = 7), the single bolus group (SB) (n = 7, 15 × 10(7) ASCs), or the divided dose group (DD) (n = 7, 5 × 10(7) ASCs/day for three consecutive days). Myocardial perfusion defect area and coronary flow reserve (CFR) were compared during the 28-day follow-up. Also, serial changes in the absolute number of circulating CD4(+) T and CD8(+) T cells were measured. RESULTS: The increases in ejection fraction were significantly greater in both the SB and the DD groups compared to the placebo group (5.4 ± 0.9%, 3.7 ± 0.7%, and -0.4 ± 0.6%, respectively), and the decrease in the perfusion defect area was significantly greater in the SB group than the placebo group (-36.3 ± 1.8 and -11.5 ± 2.8). CFR increased to a greater degree in the SB and the DD groups than in the placebo group (0.9 ± 0.2, 0.8 ± 0.1, and 0.2 ± 0.2, respectively). The circulating number of CD8(+) T cells was significantly greater in the SB and DD groups than the placebo group at day 7 (3,687 ± 317/µL, 3,454 ± 787/µL, and 1,928 ± 457/µL, respectively). The numbers of small vessels were significantly greater in the SB and the DD groups than the placebo group in the peri-infarct area. CONCLUSIONS: Both intravenous SB and DD delivery of ASCs are effective modalities for the treatment of MI in swine. Intravenous delivery of ASCs, with its immunomodulatory and angiogenic effects, is an attractive noninvasive approach for myocardial rescue.
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    Tsg-6 : an inducible mediator of paracrine anti-inflammatory and myeloprotective effects of adipose stem cells
    (2014-01-29) Xie, Jie; March, Keith Leonard, 1963-; Petrache, Irina; Clauss, Matthias A.; Broxmeyer, Hal E.
    Tumor necrosis factor-induced protein 6 (TSG-6) has been shown to mitigate inflammation. Its presence in the secretome of adipose stem / stromal cells (ASC) and its role in activities of ASC have been overlooked. This thesis described for the first time the release of TSG-6 from ASC, and its modulation by endothelial cells. It also revealed that protection of endothelial barrier function was a novel mechanism underlying the anti-inflammatory activity of both ASC and TSG-6. Moreover, TSG-6 was found to inhibit mitogen-activated lymphocyte proliferation, extending the understanding of its pleiotropic effects on major cell populations involved in inflammation. Next, enzyme-linked immunosorbent assays (ELISA) were established to quantify secretion of TSG-6 from human and murine ASC. To study the importance of TSG-6 to specific activities of ASC, TSG-6 was knocked down in human ASC by siRNA. Murine ASC from TSG-6-/- mice were isolated and the down-regulation of TSG-6 was verified by ELISA. The subsequent attempt to determine the efficacy of ASC in ameliorating ischemic limb necrosis and the role of TSG-6, however, was hampered by the highly variable ischemic tissue necrosis in the BALB/c mouse strain. Afterwards in a mouse model of cigarette smoking (CS), in which inflammation also plays an important role, it was observed, for the first time, that 3-day CS exposure caused an acute functional exhaustion and cell cycle arrest of hematopoietic progenitor cells; and that 7-week CS exposure led to marked depletion of phenotypic bone marrow stem and progenitor cells (HSPC). Moreover, a dynamic crosstalk between human ASC and murine host inflammatory signals was described, and specifically TSG-6 was identified as a necessary and sufficient mediator accounting for the activity of the ASC secretome to ameliorate CS-induced myelotoxicity. These results implicate TSG-6 as a key mediator for activities of ASC in mitigation of inflammation and protection of HSPC from the myelotoxicity of cigarette smoke. They also prompt the notion that ASC and TSG-6 might potentially play therapeutic roles in other scenarios involving myelotoxicity.
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    TSG-6 is highly expressed in human abdominal aortic aneurysms
    (Elsevier, 2017-12) Wang, S. Keisin; Xie, Jie; Green, Linden A.; McCready, Robert A.; Motaganahalli, Raghu L.; Fajardo, Andres; Babbey, Clifford C.; Murphy, Michael P.; Surgery, School of Medicine
    BACKGROUND: The formation of abdominal aortic aneurysms (AAA) is characterized by a dominance of proinflammatory forces that result in smooth muscle cell apoptosis, extracellular matrix degradation, and progressive diameter expansion. Additional defects in the antiinflammatory response may also play a role but have yet to be fully characterized. TSG-6 (TNF-stimulated gene-6) is a potent antiinflammatory protein involved in extracellular matrix stabilization and cell migration active in many pathological conditions. Here, we describe its role in AAA formation. METHODS: Blood and/or aortic tissue samples were collected from organ donors, subjects undergoing elective AAA screening, and open surgical AAA repair. Aortic specimens collected were preserved for IHC or immediately assayed after tissue homogenization. Protein concentrations in tissue and plasma were assayed by ELISA. All immune cell populations were assayed using FACS. In vitro, macrophage polarization from monocytes was performed with young, healthy donor PBMCs. RESULTS: TSG-6 was found to be abnormally elevated in both the plasma and aortic wall of patients with AAA compared with healthy and risk-factor matched non-AAA donors. We observed the highest tissue concentration of TSG-6 in the less-diseased proximal and distal shoulders compared with the central aspect of the aneurysm. IHC localized most TSG-6 to the tunica media with minor expression in the tunica adventitia of the aortic wall. Higher concentrations of both M1 and M2 macrophages where also observed, however M1/M2 ratios were unchanged from healthy controls. We observed no difference in M1/M2 ratios in the peripheral blood of risk-factor matched non-AAA and AAA patients. Interesting, TSG-6 inhibited the polarization of the antiinflammatory M2 phenotype in vitro. CONCLUSIONS: AAA formation results from an imbalance of inflammatory forces causing aortic wall infiltration of mononuclear cells leading to the vessel breakdown. In the AAA condition, we report an elevation of TSG-6 expression in both the aortic wall and the peripheral circulation.