title: Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 and Monocyte Chemoattractant Protein-1 Synergistically Regenerate Transected Rat Peripheral Nerves by Altering Macrophage Polarity.
abstract: Peripheral nerves (PNs) exhibit remarkable self-repairing reparative activity after a simple crush or cut injury. However, the neuronal transection involving a nerve gap overwhelms their repairing activity and causes persistent paralysis. Here, we show that an implantation of the serum-free conditioned medium from stem cells from human exfoliated deciduous teeth (SHED-CM) immersed in a collagen sponge into the nerve gap formed by rat facial nerves transection restored the neurological function. In contrast, SHED-CM specifically depleted of a set of anti-inflammatory M2 macrophage inducers, monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (sSiglec-9) lost the ability to restore neurological function in this model. Notably, the combination of MCP-1 and sSiglec-9 induced the polarization of M2 macrophages in vitro, resulting in the expression of multiple trophic factors that enhanced proliferation, migration, and differentiation of Schwann cells, blood vessel formation, and nerve fiber extension. Furthermore, the implantation of a collagen graft containing MCP-1/sSiglec-9 into the nerve gap induced anti-inflammatory M2 macrophage polarization, generated a Schwann-cell bridge instead of fibrotic scar, induced axonal regrowth, and restored nerve function. The specific elimination of M2 macrophages by Mannosylated-Clodrosome suppressed the MCP-1/sSiglec-9-mediated neurological recovery. Taken together, our data suggest that MCP-1/sSiglec-9 regenerates PNs by inducing tissue-repairing M2 macrophages and may provide therapeutic benefits for severe peripheral nerve injuries. Stem Cells 2017;35:641-653.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Fumiya
authors.initials: F
authors.lastname: Kano
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Kohki
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hibi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism*; D002648:Child; D005154:Facial Nerve / Q000503:physiopathology; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D009416:Nerve Regeneration; D000071446:Neuronal Outgrowth; D010525:Peripheral Nerves / Q000473:pathology* / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D012583:Schwann Cells; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D014094:Tooth, Deciduous / Q000166:cytology
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C000625502:Siglec-9 protein, rat
keywords: Dental pulp stem cells; Macrophages; Monocyte Chemoattractant Protein-1; Peripheral nerve injury; Sialic acid-binding Ig-like lectin-9