Browsing by Author "Mitha, Alim P."

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    Can Mesenchymal Stem Cells Inhibit the Formation of Saccular Aneurysms?
    (2017) Avery, Michael B; Sen, Arindom; Mitha, Alim P.; Rinker, Kristina; Eesa, Muneer
    Intracranial saccular aneurysms are pathological dilations of cerebral blood vessels that can spontaneously rupture leading to significant morbidity and mortality. Our current understanding of saccular aneurysm pathogenesis involves a complex interplay of predisposing factors and inflammatory cascades, leading to an outpouching at the site of a vessel bifurcation. While several treatments exist today, none are aimed at preventing aneurysm formation. Mesenchymal stem cells are pluripotent cells that have interesting immunomodulatory properties and have been studied in the context of many inflammatory diseases. Few studies have addressed aneurysms and suggest that these cells have the potential to be adjuvants to current treatment modalities in treating fully formed aneurysms. This thesis details the first studies investigating the use of mesenchymal stem cells in preventing the formation of saccular aneurysms. A pre- clinical trial was conducted, as well as an in vivo localization experiment to determine the potential mechanism of action.
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    Mesenchymal Stem Cell Therapy for Ischemic Tissues
    (2018-10-08) Yong, Kar Wey; Choi, Jane Ru; Mohammadi, Mehdi; Mitha, Alim P.; Sanati-Nezhad, Amir; Sen, Arindom
    Ischemic diseases such as myocardial infarction, ischemic stroke, and critical limb ischemia are immense public health challenges. Current pharmacotherapy and surgical approaches are insufficient to completely heal ischemic diseases and are associated with a considerable risk of adverse effects. Alternatively, human mesenchymal stem cells (hMSCs) have been shown to exhibit immunomodulation, angiogenesis, and paracrine secretion of bioactive factors that can attenuate inflammation and promote tissue regeneration, making them a promising cell source for ischemic disease therapy. This review summarizes the pathogenesis of ischemic diseases, discusses the potential therapeutic effects and mechanisms of hMSCs for these diseases, and provides an overview of challenges of using hMSCs clinically for treating ischemic diseases.
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    Mesenchymal Stem Cells Exhibit Both a Proinflammatory and Anti-Inflammatory Effect on Saccular Aneurysm Formation in a Rabbit Model
    (2019-07-22) Avery, Michael B.; Belanger, Brooke L.; Bromley, Amy; Sen, Arindom; Mitha, Alim P.
    Several studies have demonstrated a potential interaction between mesenchymal stem cells (MSCs) and saccular aneurysms. In this study, we sought to determine whether allogenic bone marrow-derived MSCs had the ability to prevent aneurysm formation in a known rabbit elastase aneurysm model. MSCs were injected intravenously in experimental rabbits at the time of surgical creation and two weeks postcreation and compared with control rabbits receiving vehicle injection. Angiography was used to compare aneurysm measurements four weeks postcreation, and aneurysms were harvested for histological properties. Serum was collected longitudinally to evaluate cytokine alterations. Serum from control animals was also utilized to perform in vitro tests with MSCs to compare the effect of the serologic environment in animals with and without aneurysms on MSC proliferation and cytokine production. While aneurysm morphometric comparisons revealed no differences, significant cytokine alterations were observed in vitro and in vivo, suggesting both anti-inflammatory and proinflammatory processes were occurring in the presence of MSCs. Histological analyses suggested that tunica intima hyperplasia was inhibited in the presence of MSCs.
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    Physiological oxygen conditions enhance the angiogenic properties of extracellular vesicles from human mesenchymal stem cells
    (2023-08-23) Phelps, Jolene; Hart, David A.; Mitha, Alim P.; Duncan, Neil A.; Sen, Arindom
    Abstract Background Following an ischemic injury to the brain, the induction of angiogenesis is critical to neurological recovery. The angiogenic benefits of mesenchymal stem cells (MSCs) have been attributed at least in part to the actions of extracellular vesicles (EVs) that they secrete. EVs are membrane-bound vesicles that contain various angiogenic biomolecules capable of eliciting therapeutic responses and are of relevance in cerebral applications due to their ability to cross the blood–brain barrier (BBB). Though MSCs are commonly cultured under oxygen levels present in injected air, when MSCs are cultured under physiologically relevant oxygen conditions (2–9% O2), they have been found to secrete higher amounts of survival and angiogenic factors. There is a need to determine the effects of MSC-EVs in models of cerebral angiogenesis and whether those from MSCs cultured under physiological oxygen provide greater functional effects. Methods Human adipose-derived MSCs were grown in clinically relevant serum-free medium and exposed to either headspace oxygen concentrations of 18.4% O2 (normoxic) or 3% O2 (physioxic). EVs were isolated from MSC cultures by differential ultracentrifugation and characterized by their size, concentration of EV specific markers, and their angiogenic protein content. Their functional angiogenic effects were evaluated in vitro by their induction of cerebral microvascular endothelial cell (CMEC) proliferation, tube formation, and angiogenic and tight junction gene expressions. Results Compared to normoxic conditions, culturing MSCs under physioxic conditions increased their expression of angiogenic genes SDF1 and VEGF, and subsequently elevated VEGF-A content in the EV fraction. MSC-EVs demonstrated an ability to induce CMEC angiogenesis by promoting tube formation, with the EV fraction from physioxic cultures having the greatest effect. The physioxic EV fraction further upregulated the expression of CMEC angiogenic genes FGF2, HIF1, VEGF and TGFB1, as well as genes (OCLN and TJP1) involved in BBB maintenance. Conclusions EVs from physioxic MSC cultures hold promise in the generation of a cell-free therapy to induce angiogenesis. Their positive angiogenic effect on cerebral microvascular endothelial cells demonstrates that they may have utility in treating ischemic cerebral conditions, where the induction of angiogenesis is critical to improving recovery and neurological function.
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    Predicting Thrombus Formation in Patients with Internal Carotid Artery Webs
    (2017) Ali, Syedah Salwa; Mitha, Alim P.; Di Martino, Elena; Tyberg, John V.; Egberts, Philip; Wood, David; Natale, Giovanniantonio
    Carotid webs are fibro-intimal growths affecting the internal carotid artery but are pathologically different from common atherosclerotic plaques. They cause moderate stenosis and are difficult to diagnose. However, if treated, patients present themselves again with recurrent ischemic strokes due to thrombus formation distal to the stenosis. Lack of knowledge urged the need to conduct hemodynamic analysis. This is the first study to quantify hemodynamic changes in the carotid web region. We conducted transient analysis on 3 symptomatic stroke patients with carotid webs. Carotid web region in each of the 3 carotid arteries with web was calculated with high OSI levels (0.3 approx.), low TAWSS values (less than 0.4Pa) and high RRT values. We also visualized recirculating flow behind the web during deceleration phases of cardiac cycle. All these factors reveal that carotid webs disturb blood flow patterns to cause blood stagnation, recirculation and thrombus formation to cause stroke.