RRC ID 67523
Author Matsubara K, Matsushita Y, Sakai K, Kano F, Kondo M, Noda M, Hashimoto N, Imagama S, Ishiguro N, Suzumura A, Ueda M, Furukawa K, Yamamoto A.
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.
Journal J Neurosci
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.
Volume 35(6)
Pages 2452-64
Published 2015-2-11
DOI 10.1523/JNEUROSCI.4088-14.2015
PII 35/6/2452
PMID 25673840
PMC PMC6605605
MeSH Animals Antigens, CD / metabolism Antigens, CD / pharmacology* Blood-Brain Barrier / drug effects Brain Injuries / drug therapy Cell Polarity / drug effects Cerebellum / cytology Cerebellum / drug effects Cerebellum / metabolism Chemokine CCL2 / metabolism Chemokine CCL2 / pharmacology* Child Culture Media, Conditioned Cytokines / metabolism Dental Pulp / cytology Dental Pulp / metabolism Humans Macrophages / drug effects* Mice Mice, Inbred C57BL Rats Rats, Sprague-Dawley Receptors, CCR2 / antagonists & inhibitors Sialic Acid Binding Immunoglobulin-like Lectins / metabolism Sialic Acid Binding Immunoglobulin-like Lectins / pharmacology* Spinal Cord Injuries / drug therapy* Spinal Cord Injuries / pathology Tooth, Deciduous
IF 5.674
Human and Animal Cells THP-1(RCB1189)