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Peripheral Nerve Tissue Engineering: Strategies for Repair and Regeneration

Lavasani, Mitra (2011) Peripheral Nerve Tissue Engineering: Strategies for Repair and Regeneration. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Peripheral nerve injuries are frequently encountered in trauma, sports accidents, military activities, and degenerative muscle diseases. Like most neurological conditions, patients exhibit pain, sensory and motor deficits, and functional disability. Despite all the advances in biomedical science and technology, achieving full function and organ reinnervation after these injuries remains a major challenge. High costs of healthcare, loss of employment, and social disruption have provided the impetus for active research focusing on improved strategies for repair and regeneration. Stem cell therapy holds tremendous potential for the treatment of pathologic conditions and has consequently emerged as a new area of focus in regenerative medicine. Stem cells isolated from skeletal muscle have been shown to be both pluripotent and of significant therapeutic value; however, their ability to undergo neurogenic differentiation has yet to be investigated. Here, we report that progenitor cells isolated from skeletal muscles of both mouse and human, using our established preplate technique, adopt neuronal and glial phenotypes under controlled culture conditions. Transplantation of these cells into a critical-size sciatic nerve defect allowed full nerve restoration with induction of axonal regeneration through myelin-producing Schwann-like cells. Functional recovery resulted in improved gait of cell-transplanted mice. Multi-lineage progenitor cells have been recently identified in blood vessel walls, notably in skeletal muscle, and venous grafts have been used effectively to bridge nerve defects experimentally and clinically, through unknown cellular mechanisms. In a sex-mismatch model, we identified donor-derived Y chromosomes co-localized with host Schwann cells' nuclei, indicating nerve repair through vein grafting are mediated by vascular cells. A sustained decrease in nerve regeneration by decellularized or irradiated venous grafts also highlights the contribution of blood vessel-derived cells to nerve repair. Together, these findings not only identify the cellular basis for the efficacy of therapeutic vein wrapping, but also reinforce the emerging view of muscle cell-mediated therapy for peripheral neuropathies.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmail
    Committee ChairHuard, Johnnyjhuard@pitt.edu
    Committee MemberPeault, Brunopeaultbm@upmc.edu
    Committee MemberPollett, Jonathan Bjonathan.pollett@chp.edu
    Committee MemberMarra, Kacey Gmarrakx@upmc.edu
    Committee MemberGoitz, Robert Jgoitzrj@upmc.edu
    Title: Peripheral Nerve Tissue Engineering: Strategies for Repair and Regeneration
    Status: Unpublished
    Abstract: Peripheral nerve injuries are frequently encountered in trauma, sports accidents, military activities, and degenerative muscle diseases. Like most neurological conditions, patients exhibit pain, sensory and motor deficits, and functional disability. Despite all the advances in biomedical science and technology, achieving full function and organ reinnervation after these injuries remains a major challenge. High costs of healthcare, loss of employment, and social disruption have provided the impetus for active research focusing on improved strategies for repair and regeneration. Stem cell therapy holds tremendous potential for the treatment of pathologic conditions and has consequently emerged as a new area of focus in regenerative medicine. Stem cells isolated from skeletal muscle have been shown to be both pluripotent and of significant therapeutic value; however, their ability to undergo neurogenic differentiation has yet to be investigated. Here, we report that progenitor cells isolated from skeletal muscles of both mouse and human, using our established preplate technique, adopt neuronal and glial phenotypes under controlled culture conditions. Transplantation of these cells into a critical-size sciatic nerve defect allowed full nerve restoration with induction of axonal regeneration through myelin-producing Schwann-like cells. Functional recovery resulted in improved gait of cell-transplanted mice. Multi-lineage progenitor cells have been recently identified in blood vessel walls, notably in skeletal muscle, and venous grafts have been used effectively to bridge nerve defects experimentally and clinically, through unknown cellular mechanisms. In a sex-mismatch model, we identified donor-derived Y chromosomes co-localized with host Schwann cells' nuclei, indicating nerve repair through vein grafting are mediated by vascular cells. A sustained decrease in nerve regeneration by decellularized or irradiated venous grafts also highlights the contribution of blood vessel-derived cells to nerve repair. Together, these findings not only identify the cellular basis for the efficacy of therapeutic vein wrapping, but also reinforce the emerging view of muscle cell-mediated therapy for peripheral neuropathies.
    Date: 30 June 2011
    Date Type: Completion
    Defense Date: 21 November 2008
    Approval Date: 30 June 2011
    Submission Date: 19 November 2008
    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-11192008-113051
    Uncontrolled Keywords: cell therapy; differentiation; microenvironment; muscle-derived stem cells; peripheral nerve; regeneration; Schwann cells; stem cells; tissue engineering; transformation
    Schools and Programs: Swanson School of Engineering > Bioengineering
    Date Deposited: 10 Nov 2011 15:05
    Last Modified: 14 May 2012 10:55
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-11192008-113051/, etd-11192008-113051

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