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|Title:||Differential Abilities of Acutely and Chronically Denervated Nerve Derived Schwann Cells and Skin Derived Schwann Cells to Support Axonal Regeneration and Remyelination|
|Abstract:||Despite the innate capacity of peripheral nervous system to regenerate, patients with severe nerve injury, especially those subjected to chronic nerve denervation, never regain full function, despite conventional nerve repair. The goal of this thesis is to iteratively evaluate a SC population derived from rodent and human skin towards the ultimate goal of improved autologous cell transplantation therapy to augment nerve repair. Skin derived precursors (SKPs) are multipotent stem cells with phenotypic similarities to neural crest cells. Upon transplantation into dysmyelinated or injured peripheral nerves, neonatal SKP-SCs survive, ensheath and myelinate regenerating axons and demonstrate superior indices of axonal regeneration. In this thesis, we demonstrate for the first time that, neonatal SKP-SCs therapy improves functional recovery in an array of behavioral tests in acute and delayed nerve repair models. Towards our goal of autologous therapies, we assessed adult SKP-SCs (aSKP-SCs), for promyelinating transcription factor expression, proliferation, neurite outgrowth, and remyelination. We also isolated and cultured SCs from acutely (day 5 post injury) and chronically (day 56 post injury) denervated nerves and performed detailed immunophenotypic characterization. Our data suggest that acutely denervated SCs are very potent but chronically denervated nerve SCs fail to exhibit comparable myelinating phenotype, exhibit retarded proliferation, show diminished neurite outgrowth, and demonstrate inferior in vitro/in vivo myelination as compared to acutely injured nerve SCs. We found that aSKP-SCs are very similar to acutely or embryonic nerve SCs and significantly superior to chronically denervated nerve SCs. We asked if there is a similar population of SCs in adult human skin, which may exhibit similarities to aSKP-SCs. We explored a novel population of SCs from human skin and compared them to human nerve derived SCs. Our data indicates that human skin derived SCs also express markers of pro-myelinating SC phenotype, and in preliminary experiments appears to have the capacity to ensheath and myelinate rodent axons in NOD-SCID mice. We further conclude that aSKP-SCs-like population of SCs exists in adult human skin, which shows great promise and requires further exploration to ascertain their potential for enhanced nerve repair in animal models of nerve injury, prior to clinical translation.|
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