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The Role of Matrix Metalloproteinases In Influencing Stem Cell Behavior and Skeletal Muscle Healing

Bellayr, Ian Heath (2011) The Role of Matrix Metalloproteinases In Influencing Stem Cell Behavior and Skeletal Muscle Healing. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Stem cells are highly valued for their capacity to aid in the functional recovery of damaged or diseased tissue. They are defined by their remarkable ability to maintain their undifferentiated state through countless cycles of cell division and to differentiate into variable types of specialized cells. Since ethical controversy has hindered funding for embryonic stem cell research and induced pluripotent stem cells are in the initial stages of investigations, much research has been conducted using adult stem cells. The use of adult stem cells in clinical applications is gradually becoming a reality; however, the major limitation is the difficulty to isolate, purify and expand them in culture. Matrix metalloproteinases (MMPs) have been regarded as a group of zinc-endopeptidases that influence tissue remodeling by degrading constituents of the extracellular matrix to actively promote cell proliferation, migration, apoptosis and differentiation. They have been suggested to play important roles in the regeneration of amputated newt limbs by contributing to a population of undifferentiated stem cells, called a blastema, which is likely formed by cell dedifferentiation. The research presented here builds on previous work investigating the therapeutic use of MMP1. Investigations have demonstrated the ability of MMP1 to aid in the recovery of skeletal muscle tissue by degrading fibrous scar tissue to facilitate cell migration and differentiation. This work examines the potential of MMP1 in skeletal muscle healing to stimulate stem cell behavior by the expression of certain muscle stem cell markers and its impact on cell differentiation. In addition, stem cells derived from skeletal muscle tissue were investigated to thoroughly elucidate the effect of blocking MMP signaling. MMP inhibition using GM6001 was observed to negatively impact muscle stem cell migration, stem cell associated markers and their differentiation capacity thus indicating the key role of MMPs in muscle stem cell behavior.


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    Details

    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairLi, Yongyongli@pitt.edu
    Committee MemberHuard, Johnnyjhuard@pitt.edu
    Committee MemberRoy, Parthapar19@pitt.edu
    Committee MemberShroff, Sanjeevsshroff@pitt.edu
    Committee MemberStrom, Stephenstrom@pitt.edu
    Title: The Role of Matrix Metalloproteinases In Influencing Stem Cell Behavior and Skeletal Muscle Healing
    Status: Unpublished
    Abstract: Stem cells are highly valued for their capacity to aid in the functional recovery of damaged or diseased tissue. They are defined by their remarkable ability to maintain their undifferentiated state through countless cycles of cell division and to differentiate into variable types of specialized cells. Since ethical controversy has hindered funding for embryonic stem cell research and induced pluripotent stem cells are in the initial stages of investigations, much research has been conducted using adult stem cells. The use of adult stem cells in clinical applications is gradually becoming a reality; however, the major limitation is the difficulty to isolate, purify and expand them in culture. Matrix metalloproteinases (MMPs) have been regarded as a group of zinc-endopeptidases that influence tissue remodeling by degrading constituents of the extracellular matrix to actively promote cell proliferation, migration, apoptosis and differentiation. They have been suggested to play important roles in the regeneration of amputated newt limbs by contributing to a population of undifferentiated stem cells, called a blastema, which is likely formed by cell dedifferentiation. The research presented here builds on previous work investigating the therapeutic use of MMP1. Investigations have demonstrated the ability of MMP1 to aid in the recovery of skeletal muscle tissue by degrading fibrous scar tissue to facilitate cell migration and differentiation. This work examines the potential of MMP1 in skeletal muscle healing to stimulate stem cell behavior by the expression of certain muscle stem cell markers and its impact on cell differentiation. In addition, stem cells derived from skeletal muscle tissue were investigated to thoroughly elucidate the effect of blocking MMP signaling. MMP inhibition using GM6001 was observed to negatively impact muscle stem cell migration, stem cell associated markers and their differentiation capacity thus indicating the key role of MMPs in muscle stem cell behavior.
    Date: 19 September 2011
    Date Type: Completion
    Defense Date: 22 June 2011
    Approval Date: 19 September 2011
    Submission Date: 03 June 2011
    Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-06032011-120450
    Uncontrolled Keywords: Stem Cells; Differentiation; MMPs
    Schools and Programs: Swanson School of Engineering > Bioengineering
    Date Deposited: 10 Nov 2011 14:46
    Last Modified: 10 Feb 2012 09:52
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-06032011-120450/, etd-06032011-120450

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