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IMPROVING THE CLINICAL UTILITY OF MESENCHYMAL STEM CELLS THROUGH ENHANCING CELL SURVIVAL: ENGINEERED AND CELLULAR APPROACHES

Nuschke, Austin David (2015) IMPROVING THE CLINICAL UTILITY OF MESENCHYMAL STEM CELLS THROUGH ENHANCING CELL SURVIVAL: ENGINEERED AND CELLULAR APPROACHES. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

For decades, mesenchymal stem cells have been touted as highly promising cells for use
in regenerative medicine. Their flexibility in differentiation to other cell types, paracrine abilities
in supporting angiogenesis, and modulatory behavior in inflammation have led to researchers
applying the cells across a wide variety of treatments, including skin healing, bone regeneration,
myocardial infarction repair, and others. However, a fundamental limitation in all MSC therapies
has been a lack of survival for implanted cells, preventing them from carrying out their many
beneficial functions. We have examined strategies to improve this MSC survival dilemma,
hypothesizing that a combination of engineered approaches to activate survival signaling and
modulation of autophagy to generate energy for the cell would act to improve MSC survival and
function in the face of stressors. Our results show that cell surface restriction of EGFR to
constitutively activate downstream survival signaling improves MSC longevity in two systems:
physical tethering of soluble EGF on bone regeneration scaffolds, and EGFR tethering through
EGF-like repeats of the ECM protein Tenascin C in a polymer for skin wound healing.
Additionally, we found that MSCs have a high accumulation of autophagosomes, which are
mobilized for degradation during the stress of differentiation and can be tuned to affect MSC
function in relation to differentiation. Ultimately, these strategies to alter MSC signaling and
function will be of considerable use for attempts to apply the great potential utility of MSCs to
wound healing and other contexts in biomedical science.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Nuschke, Austin Davidaun2@pitt.eduAUN20000-0002-8037-8462
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairStolz, Donna Beerdstolz@pitt.eduDSTOLZ
Thesis AdvisorWells, Alan H.wellsa@upmc.eduAHW6
Committee MemberSoto-Gutierrez, Alejandroalexsotoguti@gmail.com
Committee MemberIsenberg, Jeffrey S.jsi5@pitt.eduJSI5
Committee MemberTuan, Rocky S.rst13@pitt.eduRST13
Date: 11 December 2015
Date Type: Publication
Defense Date: 30 October 2015
Approval Date: 11 December 2015
Submission Date: 10 December 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 179
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Mesenchymal stem cell, Wound healing, EGFR, Cell survival, Autophagy, Tenascin C
Date Deposited: 11 Dec 2015 13:41
Last Modified: 19 Dec 2016 14:43
URI: http://d-scholarship.pitt.edu/id/eprint/26638

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