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Differential Abilities Of Acutely And Chronically Nerve Derived Schwann Cells And Skin Derived Schwann Cells To Support Axonal Regeneration And Remyelination
Ranjan Kumar, PhD1; Sarthak Sinha, BSc2; Jo Stratton, PhD2; Jeff Biernaskie, PhD3; Rajiv Midha, MD, MSc, FRCS(C)1
1Department of Clinical Neuroscience and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; 2Neuroscience, University of Calgary, Calgary, AB, Canada; 3Department of Comparative Biology and Experimental Medicine,
University of Calgary, Calgary, AB, Canada
Schwann cells (SCs) play a key role in supporting axonal regeneration and remyelination following a peripheral nerve injury. It is well known that outcomes following delayed nerve repair are poorer. Data suggests that in the chronically denervated nerve, SCs progressively lose their capacity to support axonal regeneration and may be less robust for remyelination. We hypothesized that recapitulating the early denervation phenotype of SCs in chronic denervation may restore remyelination and regeneration support capacity.
In this study, we compared SCs from adult rodent sciatic nerve with acute and chronic denervation, adult rodent skin derived precursor SCs (SKP-SCs), and nerve derived SCs from E16 embryonic nerve. SCs re-express key pro-myelinating transcription factors (Oct-6 and Krox-20) following acute (day 5) nerve injury, but lose this phenotype with chronic denervation (day 56) both in vivo and in cultured nerve SCs in vitro.
We found that SKP-SCs express Oct-6 and Krox-20, in vitro, to similar levels as the ones from acutely denervated nerve and significantly greatly than ones from chronically denervated nerve. We next tested and compared the various SCs for myelination both in vitro and in vivo and neurite outgrowth assay (DRG-SCs co-culture) in vitro. Additionally we compared SKP-SCs and SCs for cellular proliferation, cytokine releasing capacity and immune modulation by macrophage (M2 type) activation. Adult SKP-SCs were comparable to acutely denervated nerve SCs or embryonic nerve SCs in terms of proliferation, survival in injured nerve, in vitro and in vivo myelination, in vitro neurite outgrowth and immune modulation in injured nerve. Chronically denervated SCs were significantly poorer in all these capabilities.
From this study we conclude that: 1) temporal delay following injury results in important phenotypic changes in distal Schwann cells within the nerve and 2) adult SKP-SCs can be used as an alternate therapy to modulate immune response, restore myelination and promote axonal regeneration, in injured peripheral nerve, making these cells a favorable source of autologous cell transplantation.
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