CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration
Abstract Background Small hepatocyte-like progenitor cells (SHPCs) are hepatocytic progenitor cells that transiently form clusters in rat livers treated with retrorsine (Ret) that underwent 70% partial hepatectomy (PH). We previously reported that transplantation of Thy1+ cells obtained from d-galac...
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| Format: | Article |
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BMC
2023-05-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-023-03346-z |
| _version_ | 1827943500302254080 |
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| author | Norihisa Ichinohe Naoki Tanimizu Keisuke Ishigami Yusuke Yoshioka Naoki Fujitani Takahiro Ochiya Motoko Takahashi Toshihiro Mitaka |
| author_facet | Norihisa Ichinohe Naoki Tanimizu Keisuke Ishigami Yusuke Yoshioka Naoki Fujitani Takahiro Ochiya Motoko Takahashi Toshihiro Mitaka |
| author_sort | Norihisa Ichinohe |
| collection | DOAJ |
| description | Abstract Background Small hepatocyte-like progenitor cells (SHPCs) are hepatocytic progenitor cells that transiently form clusters in rat livers treated with retrorsine (Ret) that underwent 70% partial hepatectomy (PH). We previously reported that transplantation of Thy1+ cells obtained from d-galactosamine-treated livers promotes SHPC expansion, thereby accelerating liver regeneration. Extracellular vesicles (EVs) secreted by Thy1+ cells induce sinusoidal endothelial cells (SECs) and Kupffer cells (KCs) to secrete IL17B and IL25, respectively, thereby activating SHPCs through IL17 receptor B (RB) signaling. This study aimed to identify the inducers of IL17RB signaling and growth factors for SHPC proliferation in EVs secreted by Thy1+ cells (Thy1-EVs). Methods Thy1+ cells isolated from the livers of rats treated with d-galactosamine were cultured. Although some liver stem/progenitor cells (LSPCs) proliferated to form colonies, others remained as mesenchymal cells (MCs). Thy1-MCs or Thy1-LSPCs were transplanted into Ret/PH-treated livers to examine their effects on SHPCs. EVs were isolated from the conditioned medium (CM) of Thy1-MCs and Thy1-LSPCs. Small hepatocytes (SHs) isolated from adult rat livers were used to identify factors regulating cell growth in Thy1-EVs. Results The size of SHPC clusters transplanted with Thy1-MCs was significantly larger than that of SHPC clusters transplanted with Thy1-LSPCs (p = 0.02). A comprehensive analysis of Thy1-MC-EVs revealed that miR-199a-5p, cytokine-induced neutrophil chemoattractant-2 (CINC-2), and monocyte chemotactic protein 1 (MCP-1) were candidates for promoting SHPC growth. Additionally, miR-199a-5p mimics promoted the growth of SHs (p = 0.02), whereas CINC-2 and MCP-1 did not. SECs treated with CINC-2 induced Il17b expression. KCs treated with Thy1-EVs induced the expression of CINC-2, Il25, and miR-199a-5p. CM derived from SECs treated with CINC-2 accelerated the growth of SHs (p = 0.03). Similarly, CM derived from KCs treated with Thy1-EVs and miR-199a-5p mimics accelerated the growth of SHs (p = 0.007). In addition, although miR-199a-overexpressing EVs could not enhance SHPC proliferation, transplantation of miR-199a-overexpressing Thy1-MCs could promote the expansion of SHPC clusters. Conclusion Thy1-MC transplantation may accelerate liver regeneration owing to SHPC expansion, which is induced by CINC-2/IL17RB signaling and miR-199a-5p via SEC and KC activation. Graphical Abstract |
| first_indexed | 2024-03-13T10:16:23Z |
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| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-03-13T10:16:23Z |
| publishDate | 2023-05-01 |
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| series | Stem Cell Research & Therapy |
| spelling | doaj.art-01027d70d36941d085c6de300533cc092023-05-21T11:10:20ZengBMCStem Cell Research & Therapy1757-65122023-05-0114112210.1186/s13287-023-03346-zCINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regenerationNorihisa Ichinohe0Naoki Tanimizu1Keisuke Ishigami2Yusuke Yoshioka3Naoki Fujitani4Takahiro Ochiya5Motoko Takahashi6Toshihiro Mitaka7Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of MedicineDepartment of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of MedicineDepartment of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of MedicineDivision of Molecular and Cellular Medicine, National Cancer Center Research InstituteDepartment of Biochemistry, Sapporo Medical University School of MedicineDivision of Molecular and Cellular Medicine, National Cancer Center Research InstituteDepartment of Biochemistry, Sapporo Medical University School of MedicineDepartment of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of MedicineAbstract Background Small hepatocyte-like progenitor cells (SHPCs) are hepatocytic progenitor cells that transiently form clusters in rat livers treated with retrorsine (Ret) that underwent 70% partial hepatectomy (PH). We previously reported that transplantation of Thy1+ cells obtained from d-galactosamine-treated livers promotes SHPC expansion, thereby accelerating liver regeneration. Extracellular vesicles (EVs) secreted by Thy1+ cells induce sinusoidal endothelial cells (SECs) and Kupffer cells (KCs) to secrete IL17B and IL25, respectively, thereby activating SHPCs through IL17 receptor B (RB) signaling. This study aimed to identify the inducers of IL17RB signaling and growth factors for SHPC proliferation in EVs secreted by Thy1+ cells (Thy1-EVs). Methods Thy1+ cells isolated from the livers of rats treated with d-galactosamine were cultured. Although some liver stem/progenitor cells (LSPCs) proliferated to form colonies, others remained as mesenchymal cells (MCs). Thy1-MCs or Thy1-LSPCs were transplanted into Ret/PH-treated livers to examine their effects on SHPCs. EVs were isolated from the conditioned medium (CM) of Thy1-MCs and Thy1-LSPCs. Small hepatocytes (SHs) isolated from adult rat livers were used to identify factors regulating cell growth in Thy1-EVs. Results The size of SHPC clusters transplanted with Thy1-MCs was significantly larger than that of SHPC clusters transplanted with Thy1-LSPCs (p = 0.02). A comprehensive analysis of Thy1-MC-EVs revealed that miR-199a-5p, cytokine-induced neutrophil chemoattractant-2 (CINC-2), and monocyte chemotactic protein 1 (MCP-1) were candidates for promoting SHPC growth. Additionally, miR-199a-5p mimics promoted the growth of SHs (p = 0.02), whereas CINC-2 and MCP-1 did not. SECs treated with CINC-2 induced Il17b expression. KCs treated with Thy1-EVs induced the expression of CINC-2, Il25, and miR-199a-5p. CM derived from SECs treated with CINC-2 accelerated the growth of SHs (p = 0.03). Similarly, CM derived from KCs treated with Thy1-EVs and miR-199a-5p mimics accelerated the growth of SHs (p = 0.007). In addition, although miR-199a-overexpressing EVs could not enhance SHPC proliferation, transplantation of miR-199a-overexpressing Thy1-MCs could promote the expansion of SHPC clusters. Conclusion Thy1-MC transplantation may accelerate liver regeneration owing to SHPC expansion, which is induced by CINC-2/IL17RB signaling and miR-199a-5p via SEC and KC activation. Graphical Abstracthttps://doi.org/10.1186/s13287-023-03346-zThy1+ mesenchymal cellsExtracellular vesiclesHepatocytic progenitor cellsSmall hepatocytesmiR-199a-5pCINC-2 |
| spellingShingle | Norihisa Ichinohe Naoki Tanimizu Keisuke Ishigami Yusuke Yoshioka Naoki Fujitani Takahiro Ochiya Motoko Takahashi Toshihiro Mitaka CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration Stem Cell Research & Therapy Thy1+ mesenchymal cells Extracellular vesicles Hepatocytic progenitor cells Small hepatocytes miR-199a-5p CINC-2 |
| title | CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration |
| title_full | CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration |
| title_fullStr | CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration |
| title_full_unstemmed | CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration |
| title_short | CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration |
| title_sort | cinc 2 and mir 199a 5p in evs secreted by transplanted thy1 cells activate hepatocytic progenitor cell growth in rat liver regeneration |
| topic | Thy1+ mesenchymal cells Extracellular vesicles Hepatocytic progenitor cells Small hepatocytes miR-199a-5p CINC-2 |
| url | https://doi.org/10.1186/s13287-023-03346-z |
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