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

• Published in: Stem cells (Dayton, Ohio) Vol. 35; no. 3; pp. 641 - 653
• Main Authors: Kano, Fumiya, Matsubara, Kohki, Ueda, Minoru, Hibi, Hideharu, Yamamoto, Akihito
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.03.2017
• Subjects: Animals; Binding; Blood; Cell Differentiation; Cell Movement; Cell Polarity; Cell Proliferation; Chemokine CCL2 - metabolism; Child; Collagen; Conditioning; Crushing; Data recovery; Dental pulp; Dental pulp stem cells; Depletion; Differentiation; Facial Nerve - physiopathology; Female; Fibrosis; Ganglia, Spinal - metabolism; Grafting; Humans; Immunoglobulins; Implantation; In vitro methods and tests; Inflammation; Inflammation - pathology; Injuries; Leukocyte migration; Macrophages; Macrophages - metabolism; Macrophages - pathology; Maintenance; Mathematical models; Monocyte chemoattractant protein; Monocyte Chemoattractant Protein‐1; Nerve Regeneration; Nervous system; Neuronal Outgrowth; Paralysis; Peripheral nerve injury; Peripheral nerves; Peripheral Nerves - pathology; Peripheral Nerves - physiopathology; Polarity; Polarization; Rats, Sprague-Dawley; Recovery of Function; Regrowth; Rodents; Schwann Cells; Sialic Acid Binding Immunoglobulin-like Lectins - metabolism; Sialic acid‐binding Ig‐like lectin‐9; Signal Transduction; Stem cell transplantation; Stem cells; Stem Cells - metabolism; Teeth; Tooth, Deciduous - cytology; Trophic factors; Monocyte Chemoattractant Protein-1; Peripheral nerve injury; Macrophages; Sialic acid-binding Ig-like lectin-9; Dental pulp stem cells
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2534

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 Monocyte chemoattractant protein‐1 (MCP‐1) and sialic acid‐binding Ig‐like lectin‐9 (sSiglec‐9) secreted from dental pulp stem cells polarized bone marrow‐derived macrophages toward tissue reparative M2, which expressed multiple trophic factors that enhanced proliferation, migration, and differentiation of Schwann cells (SCs), blood vessel formation, and nerve fiber extension. Transection of facial nerve involving a nerve gap overwhelms their repairing activity, however MCP‐1/sSiglec‐9 treatment restored nerve function through the induction of M2 in the nerve gap. The M2 promoted recruitment of a number of de‐differentiated SCs, formation of a SC bridge and extension of the transected nerve fiber. Our study demonstrates the remarkable therapeutic benefits of the stem cell‐derived M2 inducers, MCP‐1 and sSiglec‐9, for regenerating severely injured peripheral nerves.