title: Secreted ectodomain of sialic acid-binding Ig-like lectin-9 and monocyte chemoattractant protein-1 promote recovery after rat spinal cord injury by altering macrophage polarity.
abstract: Engrafted mesenchymal stem cells from human deciduous dental pulp (SHEDs) support recovery from neural insults via paracrine mechanisms that are poorly understood. Here we show that the conditioned serum-free medium (CM) from SHEDs, administered intrathecally into rat injured spinal cord during the acute postinjury period, caused remarkable functional recovery. The ability of SHED-CM to induce recovery was associated with an immunoregulatory activity that induced anti-inflammatory M2-like macrophages. Secretome analysis of the SHED-CM revealed a previously unrecognized set of inducers for anti-inflammatory M2-like macrophages: monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9). Depleting MCP-1 and ED-Siglec-9 from the SHED-CM prominently reduced its ability to induce M2-like macrophages and to promote functional recovery after spinal cord injury (SCI). The combination of MCP-1 and ED-Siglec-9 synergistically promoted the M2-like differentiation of bone marrow-derived macrophages in vitro, and this effect was abolished by a selective antagonist for CC chemokine receptor 2 (CCR2) or by the genetic knock-out of CCR2. Furthermore, MCP-1 and ED-Siglec-9 administration into the injured spinal cord induced M2-like macrophages and led to a marked recovery of hindlimb locomotor function after SCI. The inhibition of this M2 induction through the inactivation of CCR2 function abolished the therapeutic effects of both SHED-CM and MCP-1/ED-Siglec-9. Macrophages activated by MCP-1 and ED-Siglec-9 extended neurite and suppressed apoptosis of primary cerebellar granule neurons against the neurotoxic effects of chondroitin sulfate proteoglycans. Our data suggest that the unique combination of MCP-1 and ED-Siglec-9 repairs the SCI through anti-inflammatory M2-like macrophage induction.
authors: Department of Oral and Maxillofacial Surgery.
authors: Kohki
authors: K
authors: Matsubara
authors: Department of Oral and Maxillofacial Surgery.
authors: Yoshihiro
authors: http://orcid.org/0000-0001-7447-061X
authors: Y
authors: Matsushita
authors: Department of Oral and Maxillofacial Surgery.
authors: Kiyoshi
authors: K
authors: Sakai
authors: Department of Oral and Maxillofacial Surgery.
authors: Fumiya
authors: F
authors: Kano
authors: Department of Oral and Maxillofacial Surgery.
authors: Megumi
authors: M
authors: Kondo
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan.
authors: Mariko
authors: http://orcid.org/0000-0002-6066-1359
authors: M
authors: Noda
authors: Biochemistry II, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan, and.
authors: Noboru
authors: N
authors: Hashimoto
authors: Orthopedic Surgery, and.
authors: Shiro
authors: S
authors: Imagama
authors: Orthopedic Surgery, and.
authors: Naoki
authors: N
authors: Ishiguro
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan.
authors: Akio
authors: A
authors: Suzumura
authors: Department of Oral and Maxillofacial Surgery.
authors: Minoru
authors: M
authors: Ueda
authors: Biochemistry II, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan, and.
authors: Koichi
authors: K
authors: Furukawa
authors: Department of Oral and Maxillofacial Surgery, akihito@med.nagoya-u.ac.jp.
authors: Akihito
authors: A
authors: Yamamoto
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy; D016764:Cell Polarity / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism / Q000494:pharmacology*; D002648:Child; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism; D003782:Dental Pulp / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000378:metabolism / Q000494:pharmacology*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology; D014094:Tooth, Deciduous
chemical_list: D015703:Antigens, CD; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D016207:Cytokines; D054390:Receptors, CCR2; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins
keywords: MCP-1; Siglec-9; anti-inflammation; dental pulp stem cells; macrophage polarity; spinal cord injury