title: Transplantation of Thy1+Cells Accelerates Liver Regeneration by Enhancing the Growth of Small Hepatocyte-Like Progenitor Cells via IL17RB Signaling.
abstract: Small hepatocyte-like progenitor cells (SHPCs) transiently form clusters in rat livers treated with retrorsine (Ret)/70% partial hepatectomy (PH). When Thy1+cells isolated from d-galactosamine-treated rat livers were transplanted into the livers of Ret/PH-treated rats, the mass of the recipient liver transiently increased during the first 30 days after transplantation, suggesting that liver regeneration was enhanced. Here we addressed how Thy1+cell transplantation stimulates liver regeneration. We found that the number and size of SHPC clusters increased in the liver at 14 days after transplantation. GeneChip analysis revealed that interleukin 17 receptor b (IL17rb) expression significantly increased in SHPCs from livers transplanted with Thy1+cells. We subsequently searched for ligand-expressing cells and found that sinusoidal endothelial cells (SECs) and Kupffer cells expressed Il17b and Il25, respectively. Moreover, extracellular vesicles (EVs) separated from the conditioned medium of Thy1+cell culture induced IL17b and IL25 expression in SECs and Kupffer cells, respectively. Furthermore, EVs enhanced IL17rb expression in small hepatocytes (SHs), which are hepatocytic progenitor cells; in culture, IL17B stimulated the growth of SHs. These results suggest that Thy1-EVs coordinate IL17RB signaling to enhance liver regeneration by targeting SECs, Kupffer cells, and SHPCs. Indeed, the administration of Thy1-EVs increased the number and size of SHPC clusters in Ret/PH-treated rat livers. Sixty days post-transplantation, most expanded SHPCs entered cellular senescence, and the enlarged liver returned to its normal size. In conclusion, Thy1+cell transplantation enhanced liver regeneration by promoting the proliferation of intrinsic hepatic progenitor cells via IL17RB signaling. Stem Cells 2017;35:920-931.
authors.affiliation: Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ichinohe
authors.affiliation: Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo, Japan.|Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanimizu
authors.affiliation: Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kon
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.affiliation: Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Mizuguchi
authors.affiliation: Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Mitaka
mesh_terms: D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D017690:Cell Transplantation; D016922:Cellular Senescence / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology; D011916:Rats, Inbred F344; D053722:Receptors, Interleukin-17 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018800:Thy-1 Antigens / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D011763:Pyrrolizidine Alkaloids; D053722:Receptors, Interleukin-17; D018800:Thy-1 Antigens; C003300:retrorsine
keywords: Hepatic progenitor cells; Interleukin 17 receptor b; Kupffer cells; Liver regeneration; Sinusoidal endothelial cells; Small hepatocytes