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.

Purification and Characterization of Schwann Cells from Adult Human Skin and Nerve

“…Irrespective of myelination capacity, the inherent capacity to support axonal growth could be sufficient impetus to supplement the chronically denervated distal nerve segment to prevent misdirection and enhance reinnervation of target organs. In addition, we have also shown that transplanted rodent adult skin-derived SCs have a remarkable capacity to enhance debris clearance (Khuong et al, 2014; Stratton et al, 2016). Taken together, it is likely that transplanted adult human SCs function in multiple ways to enhance functional outcomes.…”

“…An alternative approach might be to source SCs from a more accessible source, such as the skin (Wong et al, 2006; Biernaskie et al, 2006). Bona fide SCs can be differentiated in vitro from isolated, self-renewing skin-derived precursors (SKPs) and following transplantation have been shown to improve anatomic measures such as axon growth, myelin clearance, modulation of endogenous glial cell behavior, and remyelination, ultimately supporting improved behavioral outcomes following spinal cord and nerve injury (McKenzie et al, 2006; Biernaskie et al, 2007; Walsh et al, 2009; Walsh et al, 2010; Khuong et al, 2014; Sparling et al, 2015; Kumar et al, 2016; Stratton et al, 2016). Although the majority of these studies have been done only using rodent cells, recent work shows myelination by human skin-derived SCs (hSk-SCs) is possible from the foreskin of neonatal children (Krause et al, 2014).…”

The Effects of Epidermal Neural Crest Stem Cells on Local Inflammation Microenvironment in the Defected Sciatic Nerve of Rats

“…After PNI, inflammatory response is predominantly modulated by the infiltration and the polarization of macrophages (Chen et al, 2015), the activation of fibroblasts (Niapour et al, 2015) and SCs (Stratton et al, 2016), which is associated with a dynamic expression balance of pro- and anti-inflammatory cytokines. Macrophages have two different phenotypes, classically activated M1 macrophages possess neurotoxic effects, alternatively activated M2 macrophages promote damage repair and inhibit harmful immune responses (Fleetwood et al, 2007; Martinez et al, 2008; Kalampokis et al, 2013; Peluffo et al, 2015; Guan et al, 2016).…”

“…In the past, EPI-NCSCs had been used to repair PNI (Amoh et al, 2009), but only a few studies were designed for probing into regulatory effects of EPI-NCSCs on inflammatory response after PNI (Stratton et al, 2016). In the present study, PLGA, EPI-NCSCs and extracellular matrix (ECM), an acellular component composed of laminin, proteoglycan and entactin which play an important role in maintaining the integrity of the tissue structure and providing a proper environment for donor cell adhesion and migration (Chernousov et al, 2008), were combined to fabricate artificial nerve for repairing sciatic nerve defect of rats.…”

Schwann cells: a new player in the tumor microenvironment

“…In vitro data suggest that Schwann cells may induce M2-phenotype in macrophages, which supports efficient repair of the peripheral nerves [125, 126]. The same phenotype of tumor-associated macrophages is correlated with worse clinical prognosis in malignancies [127].…”