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The Role of Non-Myogenic Mesenchymal Stem Cells in Skeletal Muscle of Dystrophin/Utrophin Double Knockout Mice

Sohn, Jihee (2015) The Role of Non-Myogenic Mesenchymal Stem Cells in Skeletal Muscle of Dystrophin/Utrophin Double Knockout Mice. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Adult skeletal muscle possesses a remarkable regenerative ability, which largely depends on satellite cells; however, in severe muscular dystrophies, such as Duchenne muscular dystrophy (DMD), skeletal muscle integrity is compromised and the muscle is often replaced by a mixture of fibrous tissue and white adipocytes in a process termed fibro-adipogenic degeneration. The precise cellular origin and the environmental cues responsible for accumulation of fat/fibrotic tissues during the course of the disease remain unknown. Using a previously published preplate technique, two distinct populations of muscle derived cells from skeletal muscle were isolated: 1) a rapidly adhering cell population (RACs), which is non-myogenic, Pax7- and expresses the mesenchymal stem cell (MSC) marker PDGFRα, hence termed non-myogenic MSCs (nmMSCs); and 2) a slowly adhering cell population (SACs) which is Pax7+ and highly myogenic, termed myogenic progenitor cells (MPCs). In this dissertation, the role of nmMSCs in the histopathogenesis of dystrophin/utrophin double knock out (dKO) mice, an animal model of DMD, was investigated. The nmMSCs become activated during the disease progression in dKO mice, displaying increased proliferation and adipogenic, osteogenic, and fibrogenic potentials compared to age-matched WT counterparts. The activated dKO-nmMSCs also significantly reduced the myogenic potential of the dKO-MPCs, an effect, at least partially, mediated by the secreted frizzled-related protein 1 (sFRP1) released by the dKO-nmMSCs. These results suggest that nmMSCs are likely the cell source involved in the deposition of non-muscle tissues in dKO muscles and activation of nmMSCs likely exacerbates muscle wasting and degeneration during the disease progression by limiting the myogenic potential of MPCs. Interestingly, the nmMSCs also appear to play an important role in muscle regeneration after acute injury in normal WT muscle. The nmMSCs isolated from cardiotoxin injured WT muscle significantly enhanced the myogenic potential of MPCs after co-cultivation, suggesting that the nmMSCs may facilitate muscle repair in normal WT muscle. These results suggest that the muscle micro-environment plays a major role in the fate of nMMSCs. Overall, data from this dissertation proposes that a therapeutic strategy targeting nmMSCs could represent a novel treatment for DMD.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sohn, Jiheejis49@pitt.eduJIS490000-0003-4395-7438
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMars, Wendy M.wmars@pitt.eduWMARS
Thesis AdvisorHuard, Johnnyjhuard@pitt.eduJHUARD
Committee MemberWang, Bingbingwang@pitt.eduBINGWANG
Committee MemberWatkins, Simon C.swatkins@pitt.eduSWATKINS
Committee MemberTuan, Rockyrst13@pitt.eduRST13
Committee MemberMarra, Kaceymarrak@upmc.eduKGM5
Date: 4 June 2015
Date Type: Publication
Defense Date: 21 May 2015
Approval Date: 4 June 2015
Submission Date: 2 June 2015
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 125
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: stem cell, regenerative medicine, muscular dystrophy, intramuscular fat accumulation
Date Deposited: 04 Jun 2015 17:01
Last Modified: 19 Dec 2016 14:42


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