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Adipose Stromal Cell-Based Elastogenesis Therapy for Adult and Pediatric Aortic Defects

Ramaswamy, Aneesh K (2019) Adipose Stromal Cell-Based Elastogenesis Therapy for Adult and Pediatric Aortic Defects. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Aortic aneurysm (AA) is a balloon-like enlargement of the aorta exceeding 1.5-times original diameter and possessing a life-threatening risk of rupture if left untreated, representing the 15th leading cause of death in the United States. Currently, surgical intervention is governed by aortic diameter measurements, recommended after adult AA enlarge beyond a “critical diameter” of 5.5cm and pediatric AA exceed a 0.5cm/year growth rate. AA diameter growth is mediated by inflammatory damage to extracellular matrix protein elastin, responsible for aortic recoil during pulsatile blood flow. Therapeutic options for sub-critical AA are limited to “watchful waiting” imaging every 6-to-12 months to monitor diameter growth, or broad-targeted therapeutics (beta blockers, ACE inhibitors) that do not work to rebuild the aortic wall.

Recent work by our lab has shown that delivery of adipose-derived stromal cells (ASCs) can slow AA dilation and preserve elastic fibers, by either suppressing inflammatory elastin breakdown or stimulating new elastin deposition. This dissertation work utilized a versatile, fibrin-based 3D SMC aortic culture platform to test whether paracrine signaling using ASC secreted factors (ASC-SF) could induce new human elastin deposition by three different classes of aortic smooth muscle cells (SMCs): healthy adult SMCs, aneurysmal adult SMCs, and aneurysmal pediatric SMCs.

Elastin deposition was evaluated at four different points of interest on the elastogenesis cascade: elastin organizational protein transcription (generating tropoelastin, fibulin-4, and fibulin-5 coacervates/globules) [1-3], elastic fiber organization (through LTBP-4, fibulin-4, and fibulin-5 mediated deposition onto fibrillin-1 microfibrils), cross-linked elastin chemical maturity (mediated by lysyl oxidase or LOX, and lysyl oxidase-like 1 or LOXL-1), and mechanical functionality of the deposited extracellular matrix. Additionally, two methods were explored to maximize clinical translation of ASC-SF therapeutic delivery: potency of ASC-SF-derived exosomes, and a magnetic-guided periadventitial in vivo delivery system.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ramaswamy, Aneesh Kakr40@pitt.eduakr400000-0001-8944-7404
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee CoChairVorp, David Avorp@pitt.eduvorp0000-0002-6467-2151
Committee CoChairWeinbaum, Justin Sjuw51@pitt.edujuw510000-0002-0626-6083
Committee MemberBillaud, Mariebillaudm@upmc.edummb130
Committee MemberGleason, Thomas Ggleasontg@upmc.edutgg2
Committee MemberUrban, Zsolturbanz@pitt.eduurbanz
Committee MemberVande Geest, Jonathan Pjpv20@pitt.edujpv20
Date: 3 April 2019
Defense Date: 25 March 2019
Approval Date: 18 June 2019
Submission Date: 4 April 2019
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 236
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: aorta, aneurysm, elastin
Date Deposited: 18 Jun 2019 19:54
Last Modified: 18 Jun 2019 19:54
URI: http://d-scholarship.pitt.edu/id/eprint/36293

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