Transplantation of Thy1+ Cells Accelerates Liver Regeneration by Enhancing the Growth of Small Hepatocyte‐Like Progenitor Cells via IL17RB Signaling

• Published in: Stem cells (Dayton, Ohio) Vol. 35; no. 4; pp. 920 - 931
• Main Authors: Ichinohe, Norihisa, Ishii, Masayuki, Tanimizu, Naoki, Kon, Junko, Yoshioka, Yusuke, Ochiya, Takahiro, Mizuguchi, Toru, Hirata, Koichi, Mitaka, Toshihiro
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.04.2017
• Subjects: Animals; Cell Aggregation - drug effects; Cell culture; Cell proliferation; Cell Proliferation - drug effects; Cell size; Cell Size - drug effects; Cell Transplantation; Cells (biology); Cellular Senescence - drug effects; Conditioning; D-Galactosamine; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Extracellular Vesicles - drug effects; Extracellular Vesicles - metabolism; Gene Expression Regulation - drug effects; Hepatectomy; Hepatic progenitor cells; Hepatocytes; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Interleukin 1; Interleukin 17; Interleukin 17 receptor b; Interleukin-17 - metabolism; Kupffer cells; Kupffer Cells - drug effects; Kupffer Cells - metabolism; Liver; Liver - cytology; Liver regeneration; Liver Regeneration - drug effects; Liver transplantation; Male; Pyrrolizidine Alkaloids - pharmacology; Rats; Rats, Inbred F344; Receptors, Interleukin-17 - metabolism; Regeneration; Retrorsine; Self-propagating synthesis; Senescence; Signal Transduction - drug effects; Signaling; Sinusoidal endothelial cells; Small hepatocytes; Stem cell transplantation; Stem cells; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Thy-1 Antigens - metabolism; Transplantation; Small hepatocytes; Sinusoidal endothelial cells; Hepatic progenitor cells; Interleukin 17 receptor b; Liver regeneration; Kupffer cells
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2548

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 The interaction between transplanted Thy1+ and resident liver cells is summarized and illustrated. (I) When Thy1+ cells derived from GalN‐induced liver injury are transplanted into a Ret/PH‐treated rat liver, they secrete extracellular vesicles (EVs) while trapped in the liver sinusoids. EVs induce the proliferation of host hepatocytes with the ability of hepatic progenitor cells, SHPCs, to exhibit IL17RB. EVs also induce IL17B and IL25 production in SECs and Kupffer cells, respectively. (II) Secreted IL17B and IL25 cooperate with growth factors, such as HGF and EGF, to induce rapid proliferation in neighboring SHPCs, leading to the formation of SHPC clusters. (III) The many large SHPC clusters induced by cytokines may contribute to liver enlargement observed post‐transplantation. (IV) After 1 month, a proportion of SHPCs enter cellular senescence. Two months post‐transplantation, SHPC clusters become indistinguishable from surrounding hepatocytes, and liver size returns to normal.