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

J Neurosci. 2015 Feb 11;35(6):2452-64. doi: 10.1523/JNEUROSCI.4088-14.2015.


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.

Keywords: MCP-1; Siglec-9; anti-inflammation; dental pulp stem cells; macrophage polarity; spinal cord injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Antigens, CD
  • CCL2 protein, human
  • Chemokine CCL2
  • Culture Media, Conditioned
  • Cytokines
  • Receptors, CCR2
  • SIGLEC9 protein, human
  • Sialic Acid Binding Immunoglobulin-like Lectins