title: The immunomodulatory properties of adult skin-derived precursor Schwann cells: implications for peripheral nerve injury therapy.
abstract: Skin-derived precursor Schwann cell (SKPSC) therapy has been identified as a potentially beneficial treatment for peripheral nerve injuries. One hypothesised mechanism by which SKPSCs enhance recovery is via the modulation of macrophages. In the present study, we investigated the immunomodulatory properties of adult rat SKPSCs, and demonstrated that these cells expressed a battery of cytokines, including interferon-γ (IFN-γ), interleukin (IL)-1β, and, most abundantly, IL-6. Whereas macrophages exposed to depleted or fibroblast-conditioned medium secreted minimal amounts of tumor necrosis factor-α (TNF-α), in the presence of SKPSC-conditioned medium, macrophages secreted > 500 pg/mL TNF-α. Following the transplantation of SKPSCs into injured rat sciatic nerves, we observed an SKPSC density-dependent increase in the number of macrophages (Pearson's r = 0.66) and an SKPSC density-dependent decrease in myelin debris (Pearson's r = -0.68). To determine the effect of IL-6 in a proinflammatory context, macrophage cultures were primed with either lipopolysaccharide (LPS)/IFN-γ/IL-1β or LPS/IFN-γ/IL-1β + IL-6, and this showed a 212% and 301% increase in the number of inducible nitric oxide synthase (iNOS)-positive proinflammatory macrophages respectively. In contrast to neurons exposed to conditioned medium from unprimed macrophages, neurons treated with conditioned medium from proinflammatory-primed macrophages showed a 13-26% reduction in neurite outgrowth. Anti-IL-6 antibody combined with SKPSC transplant therapy following nerve injury did not alter macrophage numbers or debris clearance, but instead reduced iNOS expression as compared with SKPSC + IgG-treated rats. SKPSC + anti-IL-6 treatment also resulted in a two-fold increase in gastrocnemius compound muscle action potential amplitudes as compared with SKPSC + IgG treatment. Understanding the mechanisms underlying immunomodulatory aspects of SKPSC therapy and developing approaches to manipulate these responses are important for advancing Schwann cell-based therapies.
authors.affiliation: Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.|Comparative Biology and Experimental Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.|Hotchkiss Brain Institute, Calgary, AB, Canada.
authors.forename: Jo Anne
authors.initials: JA
authors.lastname: Stratton
authors.affiliation: Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.|Comparative Biology and Experimental Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.|Hotchkiss Brain Institute, Calgary, AB, Canada.
authors.forename: Prajay T
authors.initials: PT
authors.lastname: Shah
authors.affiliation: Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.|Comparative Biology and Experimental Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.|Hotchkiss Brain Institute, Calgary, AB, Canada.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Comparative Biology and Experimental Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.|Hotchkiss Brain Institute, Calgary, AB, Canada.
authors.forename: Morgan G
authors.initials: MG
authors.lastname: Stykel
authors.affiliation: Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shapira
authors.affiliation: Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.|Hotchkiss Brain Institute, Calgary, AB, Canada.
authors.forename: Joey
authors.initials: J
authors.lastname: Grochmal
authors.affiliation: Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.|Hotchkiss Brain Institute, Calgary, AB, Canada.
authors.forename: Gui Fang
authors.initials: GF
authors.lastname: Guo
authors.affiliation: Comparative Biology and Experimental Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.|Hotchkiss Brain Institute, Calgary, AB, Canada.
authors.forename: Jeff
authors.initials: J
authors.lastname: Biernaskie
authors.affiliation: Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.|Hotchkiss Brain Institute, Calgary, AB, Canada.|Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Midha
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology*; D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009186:Myelin Sheath / Q000378:metabolism; D009416:Nerve Regeneration; D009474:Neurons / Q000187:drug effects; D059348:Peripheral Nerve Injuries / Q000628:therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D012583:Schwann Cells / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D012867:Skin / Q000166:cytology
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines
keywords: cytokines; interleukin-6; macrophages; neutralisation; rat