title: Secreted Ectodomain of SIGLEC-9 and MCP-1 Synergistically Improve Acute Liver Failure in Rats by Altering Macrophage Polarity.
abstract: Effective treatments for acute liver failure (ALF) are still lacking. We recently reported that a single intravenous administration of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) into the D-galactosamine (D-Gal)-induced rat ALF model improves the liver injury. However, the specific factors in SHED-CM that are responsible for resolving ALF remain unclear. Here we found that depleting SHED-CM of two 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)-abolished its ability to resolve rat ALF. Furthermore, treatment with MCP-1/sSiglec-9 alone dramatically improved the survival of ALF rats. This treatment induced anti-inflammatory M2, suppressed hepatocyte apoptosis, and promoted hepatocyte proliferation. Treatment with an M2-depletion reagent (mannosylated clodronate liposomes) suppressed the recovery. In addition, MCP-1 and sSiglec-9 synergistically promoted the M2 differentiation of bone marrow-derived macrophages via CCR2, accompanied by the production of multiple liver-regenerating factors. The conditioned medium from MCP-1/sSiglec-9-activated M2 macrophages, but not from interleukin-4-induced ones, suppressed the D-Gal- and LPS-induced apoptosis of primary hepatocytes and promoted their proliferation in vitro. The unique combination of MCP-1/sSiglec-9 ameliorates rat ALF by inhibiting hepatocellular apoptosis and promoting liver regeneration through the induction of anti-inflammatory/tissue-repairing M2 macrophages.
authors.affiliation: Department of Gastroenterology and Hepatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Gastroenterology and Hepatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ishigami
authors.affiliation: Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsushita
authors.affiliation: Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Kohki
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Department of Gastroenterology and Hepatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hibi
authors.affiliation: Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Gastroenterology and Hepatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hirooka
authors.affiliation: Department of Gastroenterology and Hepatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.|Department of Oral histology, Institute of Biomedical Science, Tokushima University Graduate School, 3-18-5 Kuramoto-cho, Tokushima 770-8504, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism*; D016895:Culture Media, Serum-Free; D005260:Female; D007249:Inflammation / Q000150:complications / Q000378:metabolism; D017114:Liver Failure, Acute / Q000150:complications / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology; D014080:Tooth Exfoliation; D014094:Tooth, Deciduous / Q000166:cytology
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016895:Culture Media, Serum-Free; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C000625502:Siglec-9 protein, rat