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
|
Resource |
Human and Animal Cells |
THP-1(RCB1189) |