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The Role of Stress Resistance in Cell Transplantation Efficacy for Muscle Regeneration

Vella II, Joseph Bayer (2011) The Role of Stress Resistance in Cell Transplantation Efficacy for Muscle Regeneration. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Despite the regenerative capacity of skeletal muscle, chronic myopathy and muscle trauma present significant clinical problems with limited therapeutic options. Myogenic cell therapies are being actively investigated to mitigate muscle degeneration that otherwise progresses to fibrosis and long-term loss of function. The rationale for this strategy is based on augmenting the native myogenic progenitor or stem cell reserve, populated by satellite cells, by transplanting myogenic cells into the injured muscle. However, engraftment efficiency in myogenic cell transplantation is impaired by rapid cell death, which represents a precipitous loss of cell viability within 48hrs of injection, therefore severely limiting engraftment and tissue regeneration. Upon transplantation, cells experience a host response of rapid inflammation; an environment of oxidative and inflammatory stress that may cause a dramatic loss in cell viability. This effect may determine the regeneration capacity irrespective of the cell's multilineage differentiation potential. Our lab has isolated and characterized multiple populations of myogenic progenitors from murine and human skeletal muscle, including the muscle derived stem cell (MDSC) isolated by a modified preplate technique. In our studies of MDSCs, we observed an increase in post-transplantation survival and skeletal muscle regeneration capacity over that of early preplate myoblasts. Furthermore, a strong correlation of improved survival and regeneration with inflammatory and oxidative stress resistance emerged. In this dissertation, we examined the role stress resistance and survival during myogenic differentiation of MDSCs. By treating the transplanted cells with a membrane permeable reactive oxygen species scavenger, XJB-5-131, prior to transplantation, the survival and myogenic differentiation capacity under stress conditions was significantly improved. Furthermore, we isolated a novel sub-population of muscle derived cells with elevated stress resistance from murine and human skeletal muscle by their enhanced aldehyde dehydrogenase activity. ALDHlo and ALDHhi cells were characterized in terms of their myogenic potential and stress tolerance in vitro and muscle regeneration capacity in vivo. These studies are aimed at understanding the importance of survival and stress tolerance of transplanted cells in skeletal muscle cell therapy and how this tolerance modifies the efficacy of cell therapy.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Vella II, Joseph
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberHuard, Johnnyjhuard@pitt.eduJHUARD
Committee MemberPiganelli, Jonathonjdp51@pitt.eduJDP51
Committee MemberRoy, Parthapar19@pitt.eduPAR19
Committee MemberLi, Yongyongli@pitt.eduYONGLI
Date: 26 January 2011
Date Type: Completion
Defense Date: 16 November 2010
Approval Date: 26 January 2011
Submission Date: 3 November 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
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: cell therapy; inflammation; muscle; oxidative stress; stem cells
Other ID:, etd-11032010-155528
Date Deposited: 10 Nov 2011 20:04
Last Modified: 15 Nov 2016 13:51


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