Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treatment of Small Abdominal Aortic Aneurysm

Wang, S. Keisin; Green, Linden A.; Gutwein, Ashley R.; Drucker, Natalie A.; Motaganahalli, Raghu L.; Fajardo, Andres; Babbey, Clifford M.; Murphy, Michael P.

doi:10.1016/j.avsg.2017.08.044

Cited by 25 publications

(22 citation statements)

References 30 publications

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“…Indeed, it has been demonstrated that the administration of MSCs‐CM was as effective as MSC treatment itself in various diseases . Recently, MSCs have been shown to prevent AA formation and progression in a variety of AA models . In the present study, we investigated the effects and mechanisms of the administration of MSCs‐CM on AngII‐induced AA in apoE −/− mice.…”

Section: Discussionmentioning

confidence: 94%

“…14,15,17 Recently, MSCs have been shown to prevent AA formation and progression in a variety of AA models. [10][11][12]25 In the present study, we investigated the effects and Macrophages are essential mediators of the inflammatory response and play an important role in inflammation-associated diseases. Previous studies have suggested that macrophage polarization may be involved in the development of AA.…”

Section: Discussionmentioning

confidence: 99%

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Mesenchymal stem cell–derived conditioned medium attenuate angiotensin II‐induced aortic aneurysm growth by modulating macrophage polarization

Zhou

Cheng

et al. 2019

J Cellular Molecular Medi

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Mesenchymal stem cells (MSCs) exhibit therapeutic benefits on aortic aneurysm (AA); however, the molecular mechanisms are not fully understood. The current study aimed to investigate the therapeutic effects and potential mechanisms of murine bone marrow MSC (BM‐MSCs)–derived conditioned medium (MSCs‐CM) on angiotensin II (AngII)‐induced AA in apolipoprotein E‐deficient (apoE−/−) mice. Murine BM‐MSCs, MSCs‐CM or control medium were intravenously administrated into AngII‐induced AA in apoE−/− mice. Mice were sacrificed at 2 weeks after injection. BM‐MSCs and MSCs‐CM significantly attenuated matrix metalloproteinase (MMP)‐2 and MMP‐9 expression, aortic elastin degradation and AA growth at the site of AA. These treatments with BM‐MSCs and MSCs‐CM also decreased Ly6chigh monocytes in peripheral blood on day 7 and M1 macrophage infiltration in AA tissues on day 14, whereas they increased M2 macrophages. In addition, BM‐MSCs and MSCs‐CM reduced MCP‐1, IL‐1Ra and IL‐6 expression and increased IL‐10 expression in AA tissues. In vitro, peritoneal macrophages were co‐cultured with BM‐MSCs or fibroblasts as control in a transwell system. The mRNA and protein expression of M2 macrophage markers were evaluated. IL‐6 and IL‐1β were reduced, while IL‐10 was increased in the BM‐MSC systems. The mRNA and protein expression of M2 markers were up‐regulated in the BM‐MSC systems. Furthermore, high concentration of IGF1, VEGF and TGF‐β1 was detected in MSCs‐CM. Our results suggest that MSCs‐CM could prevent AA growth potentially through regulating macrophage polarization. These results may provide a new insight into the mechanisms of BM‐MSCs in the therapy of AA.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cell–derived conditioned medium attenuate angiotensin II‐induced aortic aneurysm growth by modulating macrophage polarization

Zhou

Cheng

et al. 2019

J Cellular Molecular Medi

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“…Compared to studies with local implantation of MSCs [ 15 , 20 ], intravenous injection of MSCs represents the minimum invasive systematic route for cellular therapy, and has been previously shown to be effective in different AAA models [ 16 , 18 , 34 ]. In addition, a randomized controlled trail investigating MSCs in small human AAA also applied intravenous administration [ 58 ], which further arise the clinical convenience and feasibility of intravenous administration.…”

Section: Discussionmentioning

confidence: 99%

Human Umbilical Cord Mesenchymal Stem Cells Attenuate Abdominal Aortic Aneurysm Progression in Sprague-Dawley Rats: Implication of Vascular Smooth Muscle Cell Phenotypic Modulation

Wen

Wang

Gong

et al. 2020

Stem Cells and Development

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Abdominal aortic aneurysm (AAA) is life-threatening, for which efficient nonsurgical treatment strategy has not been available so far. Several previous studies investigating the therapeutic effect of mesenchymal stem cells (MSCs) in AAA indicated that MSCs could inhibit aneurysmal inflammatory responses and extracellular matrix destruction, and suppress aneurysm occurrence and expansion. Vascular smooth muscle cell (VSMC) phenotypic plasticity is reported to be predisposed in AAA initiation and progression. However, little is known about the effect of MSCs on VSMC phenotypic modulation in AAA. In this study, we investigate the therapeutic efficacy of umbilical cord mesenchymal stem cells (UC-MSCs) in elastase-induced AAA model and evaluate the effect of UC-MSC on VSMC phenotypic regulation. We demonstrate that the intravenous injection of UC-MSC attenuates elastase-induced aneurysmal expansion, reduces elastin degradation and fragmentation, inhibits MMPs and TNFa expression, and preserves and/or restores VSMC contractile phenotype in AAA. Taken together, these results highlight the therapeutic and VSMC phenotypic modulation effects of UC-MSC in AAA progression, which further indicates the potential of applying UC-MSC as an alternative treatment candidate for AAA.

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“…This antigen-specific regulatory T lymphocyte primarily elaborates IL-10, a potent anti-inflammatory cytokine in response to antigen recognition. 9 Not only was this Tr1 population depleted, but it was also less functional in terms of ability to migrate to a stimulus, secrete IL-10 when activated, and polarize monocytes toward the anti-inflammatory M2 macrophage. Therefore, we hypothesized that this deficit of IL-10 and Tr1, and inability control aortic wall inflammation, may be the driver for initial aortic ectasia and eventual aneurysm formation.…”

Section: Circulation Research March 30 2018mentioning

confidence: 99%

“…9 These potential participants are identified through US Preventative Task Force-recommended AAA sonographic screenings for patients aged 65 years, an examination provided for no cost as a part of the Welcome to Medicare package. In this study, 36 patients are randomized at a 1:1:1 ratio to placebo, 1×10 6 MSCs/kg, or 3×10 6 MSCs/kg through a large bore peripheral IV and followed for 5 years to determine changes in aortic diameter, cytokine expression, and circulating immune cell expression.…”

Section: Circulation Research March 30 2018mentioning

confidence: 99%

Immune Modulation as a Treatment for Abdominal Aortic Aneurysms

Wang

Murphy

2018

Circulation Research

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In the United States, >200 000 new patients are diagnosed with abdominal aortic aneurysm (AAA) each year. Consequently, >40 000 highly morbid aortic reconstructions are performed each year to prevent aneurysm rupture, a catastrophic event associated with near-certain mortality. No pharmaceutical currently exists to slow aneurysm growth, but a 50% reduction in diameter growth per annum could halve the number of aortic reconstructions required. Therefore, successful use of cell therapy to modulate chronic inflammation hallmark to AAA to slow diameter expansion represents a potentially paradigmaltering treatment.There continues to be no US Food and Drug-approved medication to slow or stop AAA growth. This deficit is certainly not because of a lack of effort over the previous decades. Initial investigations focused on the reduction of mechanical stress through decreasing blood pressure and sac pressurization cycles; however, clinical trials investigating drugs, such as, angiotensin II-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers, all failed to demonstrate a therapeutic reduction of diameter growth compared with placebo. Next, the inhibition of matrix metalloproteinases was trialed with doxycycline, an antibiotic inhibitor of matrix metalloproteinases 2 and 9. Doxycycline also treats species of Chlamydia, which were isolated from the aortic walls of a minority of aneurysmal arteries. Although initial uncontrolled results were promising, therapeutic response was not replicated in large randomized studies. Last, aortic wall inflammation was targeted using statins, a ubiquitous anti-inflammatory, lipid-lowering drug to limited success. The discovery of a nonsurgical treatment for AAA is contingent on the robust understanding of disease pathogenesis, which continues to be nebulous at best.AAA risk factors, such as, tobacco abuse, advancing age, uncontrolled hypertension, male sex, and white ethnicity, have all been well described but fail to provide evidence elucidating pathogenesis. Regardless, existing evidence implicates that disease initiation is multifactorial with a strong genetic element.There has been a focus of late toward the role of autoimmune mechanisms in AAA formation. The characterization of aortic wall inflammation consisting of mononuclear infiltrates, immunoglobulins, cytokines, and proteases implicate both a host innate and adaptive response. Of note, concentrations of CD4 + T cells have been recently discovered in the periadventitial vascular-associated lymphatic tissue expressing identical T cell receptors, against a currently unknown antigen, and therefore clonally expanded, providing crucial evidence for AAA as an autoimmune disease.1 Moreover, interleukin (IL)-17, a cytokine elaborated from the antigen-specific Th17 lymphocyte and overexpressed in autoimmune disorders, is highly expressed in the AAA condition. Abrogation of this cytokine, in animal models, has demonstrated efficacy in decreasing aneurysm diameter growth.2 Although several putative autoantigens have b...

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Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treatment of Small Abdominal Aortic Aneurysm

Cited by 25 publications

References 30 publications

Mesenchymal stem cell–derived conditioned medium attenuate angiotensin II‐induced aortic aneurysm growth by modulating macrophage polarization

Mesenchymal stem cell–derived conditioned medium attenuate angiotensin II‐induced aortic aneurysm growth by modulating macrophage polarization

Human Umbilical Cord Mesenchymal Stem Cells Attenuate Abdominal Aortic Aneurysm Progression in Sprague-Dawley Rats: Implication of Vascular Smooth Muscle Cell Phenotypic Modulation

Immune Modulation as a Treatment for Abdominal Aortic Aneurysms

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