Date of Award

Summer 1-1-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy In Applied Biomedical Engineering Degree

Department

Chemical And Biomedical Engineering

First Advisor

Ramamurthi, Anand

Second Advisor

Margot Damaser

Third Advisor

Joanne Belovich

Abstract

egenerative repair of the elastic matrix is naturally limited due to the intrinsically poor elastogenicity of adult vascular smooth muscle cells. Therefore, when the elastic matrix, which provides tissue stretch and recoil are disrupted in a proteolytic milieu, such as in Abdominal Aortic Aneurysms (AAAs), localized rupture-prone expansions of the aorta, the damage is difficult to reverse. This demands providing an external, pro-elastin regenerative- and anti-proteolytic stimuli to aneurysmal SMCs in the AAA wall towards reinstating matrix structure in the aorta wall. Introducing alternative phenotypes of highly elastogenic and contractile cells into the AAA wall, capable of providing such cues, proffers attractive prospects for AAA treatment. In this regard, our previous studies demonstrated superior elastogenicity of bone marrow mesenchymal stem cell (BM-MSC)-derived SMCs (BM-SMCs) and their ability to provide pro-elastogenic and anti-proteolytic stimuli to aneurysmal SMCs in vitro. However, for cell therapy a large cell inoculate is required for which these derived cells must be cultured extensively as well as retain their superior elastogenicity and antiproteolytic benefit in long term culture as well as in vivo collagenous environment which is not conducive to elastogenesis. Accordingly, in this study we assessed the proelastogenic and antiproteolytic benefits of the BM-MSC derived cells in vitro and in vivo. The overall goal of this dissertation is to understand the pro-elastogenic and anti-proteolytic behavior of BM-MSCs derived SMCs in vitro and in vivo towards their xv implication as an alternative cell source for elastin regenerative repair in AAAs. Our results indicate that the stem cell derivatives retain their phenotype and superior elastogenic and anti-proteolytic properties in 2D as well as 3D collagenous culture in vitro. The results of our in vivo studies indicate that the stem cell derivatives (a) possess natural homing abilities similar to the undifferentiated BM-MSCs, (b) exhibit higher retention upon localization in the aneurysmal aorta compared to undifferentiated BMMSCs, (c) downregulate expression of several inflammatory and pro-apoptotic cytokines that are upregulated in the AAA wall, contributing to accelerated elastic matrix breakdown and suppression of elastic fiber reassembly, repair and crosslinking and (d) improve elastic matrix content and structure in the AAA wall towards slowing the growth of AAAs. Our study provides initial evidence of the in vivo elastic matrix reparative benefits of BM-MSC-derived SMCs and their utility as cell therapy to reverse pathophysiology of proteolytic conditions like AAAs.

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