研究者詳細 - 水口　徹

論文 - 水口　徹

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An Optimal Timing for Removing a Drain After Breast Surgery: A Systematic Review and Meta-Analysis.

Hiroaki Shima, Goro Kutomi, Kiminori Sato, Yoko Kuga, Asaka Wada, Fukino Satomi, Satoko Uno, Noriko Nisikawa, Hidekazu Kameshima, Tosei Ohmura, Toru Mizuguchi, Ichiro Takemasa

The Journal of surgical research 267 267 - 273 2021年11月 [国際誌]

BACKGROUND: In clinical practice, drains had been routinely used for reducing seroma formation after breast surgery. However, an optimal timing to remove drains does not identify yet. METHODS: This study aimed to compare the clinical outcome, such as seroma formation, surgical site infection (SSI), and a length of hospital stay between early removal and late removal. A systematic review was performed using PubMed, MEDLINE, and the Cochrane Library. Breast cancer patients who received surgery using drains were eligible. Those parameters were compared between early vs late removal. RESULTS: Eleven studies included in this meta-analysis. Seroma formation in the early removal group was significantly higher than the one in the late removal group (RR = 1.58: 95%CI [1.25-2.01], P = 0.0001), meanwhile no significant difference was found among the groups for SSI (RR = 0.82: 95%CI [0.51-1.31], P= 0.40). A length of hospital stay in the early removal group was also significantly shorter than late removal (RR -3.31: 95%CI [-5.13-1.49], P = 0.0004). CONCLUSIONS: Seroma formation was significantly higher in patients who had early drain removal. Conversely, SSI incidence was low, and early removal did not increase SSI incidence. In conclusion, early drain removal has no proved clinical benefit in these settings besides reduction of hospital stays.

DOI PubMed

Maturation of robotic liver resection during the last decade: A systematic review and meta-analysis

Tomohiro Ishinuki, Shigenori Ota, Kohei Harada, Makoto Meguro, Masaki Kawamoto, Goro Kutomi, Hiroomi Tatsumi, Keisuke Harada, Koji Miyanishi, Ichiro Takemasa, Toshio Ohyanagi, Thomas T Hui, Toru Mizuguchi

World Journal of Meta-Analysis ( Baishideng Publishing Group Inc. ) 9 ( 5 ) 462 - 473 2021年10月

DOI

Major hepatectomyにおけるGeriatric Nutritional Risk Index(GNRI)で評価した栄養状態と短期予後との関連に関する検討

永山稔, 木村康利, 今村将史, 久木田和晴, 村上武志, 加藤透, 伊東竜哉, 信岡隆幸, 水口徹, 竹政伊知朗

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 82 ( 増刊 ) S773 - S773 2021年10月

Extracellular vesicles containing miR-146a-5p secreted by bone marrow mesenchymal cells activate hepatocytic progenitors in regenerating rat livers.

Norihisa Ichinohe, Masayuki Ishii, Naoki Tanimizu, Toru Mizuguchi, Yusuke Yoshioka, Takahiro Ochiya, Hiromu Suzuki, Toshihiro Mitaka

Stem cell research & therapy 12 ( 1 ) 312 - 312 2021年05月 [国際誌]

BACKGROUND: Small hepatocyte-like progenitor cells (SHPCs) appear to form transient clusters in rat livers treated with retrorsine (Ret) and 70% partial hepatectomy (PH). We previously reported that the expansion of SHPCs was amplified in Ret/PH-treated rat livers transplanted with Thy1+ cells derived from D-galactosamine-treated injured livers. Extracellular vesicles (EVs) produced by hepatic Thy1+ donor cells activated SHPCs via interleukin (IL)-17 receptor B signaling. As bone marrow-derived mesenchymal cells (BM-MCs) also express Thy1, we aimed to determine whether BM-MCs could also promote the growth of SHPCs. METHODS: BM-MCs were isolated from dipeptidyl-peptidase IV (DPPIV)-positive rats. BM-MCs or BM-MC-derived EVs were administered to DPPIV-negative Ret/PH rat livers, and the growth and the characteristics of SHPC clusters were evaluated 14 days post-treatment. miRNA microarrays and cytokine arrays examined soluble factors within EVs. Small hepatocytes (SHs) isolated from an adult rat liver were used to identify factors enhancing hepatocytic progenitor cells growth. RESULTS: The recipient's livers were enlarged at 2 weeks post-BM-MC transplantation. The number and the size of SHPCs increased remarkably in livers transplanted with BM-MCs. BM-MC-derived EVs also stimulated SHPC growth. Comprehensive analyses revealed that BM-MC-derived EVs contained miR-146a-5p, interleukin-6, and stem cell factor, which could enhance SHs' proliferation. Administration of EVs derived from the miR-146a-5p-transfected BM-MCs to Ret/PH rat livers remarkably enhanced the expansion of SHPCs. CONCLUSIONS: miR-146a-5p involved in EVs produced by BM-MCs may play a major role in accelerating liver regeneration by activating the intrinsic hepatocytic progenitor cells.

DOI PubMed

外科周術期感染予防に関するガイドライン SSI予防の周術期管理ガイドライン発表から2年経過して

水口徹, 石貫智裕, 太田盛道, 沖田憲司, 西舘敏彦, 久野芳佳, 首藤英里香, 城丸瑞恵, 堀口雅美, 秦史壮, 角隆臣, 大柳俊夫, 久冨五郎, 永山稔, 竹政伊知朗

日本外科系連合学会誌 ( 日本外科系連合学会 ) 46 ( 3 ) 323 - 323 2021年05月

Tomohiro Ishinuki, Shigenori Ota, Kohei Harada, Hiroomi Tatsumi, Keisuke Harada, Koji Miyanishi, Minoru Nagayama, Ichiro Takemasa, Toshio Ohyanagi, Thomas T Hui, Toru Mizuguchi

World Journal of Meta-Analysis ( Baishideng Publishing Group Inc. ) 9 ( 1 ) 88 - 100 2021年02月

DOI

Surgical advantage of ultrasonically activated devices during axillary lymph node dissection for breast cancer

Goro Kutomi, Hiroaki Shima, Hideki Maeda, Fukino Satomi, Asaka Wada, Kiminori Sato, Toru Mizuguchi, Ichiro Takemasa

International Surgery ( International College of Surgeons ) 105 ( 1-3 ) 623 - 627 2021年

Purposes: Axillary dissection is the gold standard for axillary lymph node metastasis in breast cancer patients. We compared surgical outcomes between ultrasonically activated devices (USADs) and thermal scalpel (TS) during axillary lymph node dissection in breast cancer patients. Methods:We conducted a retrospective analysis for 73 patients using TS between June 2012 to May 2016 and 63 patients using USADs between June 2016 to January 2019 in the breast cancer patients who received axillary dissection. Surgical outcomes were compared among the groups statistically. Results: Median operative time in the USAD group was significantly shorter than in the TS group (136 versus 182 minutes, P , 0.001). Intraoperative blood loss in the USAD group was also significantly lower than in the TS group (35 versus 120 mL, P , 0.001). Furthermore, the total drainage discharge in the USAD group was also significantly lower than in the TS group (570 versus 700 mL, P 0.016). The lymphedema frequency in the USAD group was significantly less than in the TS groups (1 of 63 versus 7 of 73, P 0.0296). Conclusion: The USADs could improve surgical outcomes, such as lymphedema, for axillary dissection of the breast cancer surgery compared with TS.

DOI

Nature of the liver volume depending on the gender and age assessing volumetry from a reconstruction of the computed tomography.

Kohei Harada, Tomohiro Ishinuki, Yoshiya Ohashi, Takeo Tanaka, Ayaka Chiba, Kanako Numasawa, Tatsuya Imai, Shun Hayasaka, Takahito Tsugiki, Koji Miyanishi, Minoru Nagayama, Ichiro Takemasa, Junji Kato, Toru Mizuguchi

PloS one 16 ( 12 ) e0261094 2021年 [査読有り] [国際誌]

Although the liver is a regenerating organ, excessive loss of liver volume (LV) can cause fatal liver failure. It is unclear whether LV is correlated with age; however, it is known that liver function decreases with age. In addition, the gender-related role of LV remains unclear. This study aimed to investigate the changes in LV by age and gender. Between January and December 2018, 374 consecutive patients who underwent abdominal multidetector computed tomography (MDCT) for any abdominal examinations were enrolled. LV was evaluated using MDCT. The relationship between the LV and body mass index (BMI), body surface area (BSA), age, and gender was investigated. The modified LV (mLV) was calculated by a formula measured LV × 1.5/BSA. LV correlated to BSA more than to BMI in both the males (R: 0.559 vs. 0.416) and females (R: 0.479 vs. 0.300) in our study. Age was negatively correlated to LV and BSA, and correlated to LV more than to BSA in males (R: 0.546 vs. 0.393) and females (R: 0.506 vs. 0.385). In addition, the absolute slope between age and LV in the males was higher than that in the females (14.1 vs. 10.2, respectively). Furthermore, the absolute slope of age and mLV in the males was slightly higher than in the females (9.1 vs. 7.3, respectively). In conclusion, LV in the normal liver is correlated to age rather than the one in the diseased liver. Liver volume in the males decreased more with age than LV in the females.

DOI PubMed

Effect of Rikkunshito, a Traditional Japanese Herbal Medicine, on Delayed Gastric Emptying and Oral Dietary Intake After Pancreaticoduodenectomy: A Prospective, Randomized, Single-Center, Open-Labeled Study.

Hiroshi Yamaguchi, Yasutoshi Kimura, Masafumi Imamura, Minoru Nagayama, Tatsuya Ito, Daisuke Kyuno, Tsuyoshi Kono, Akina Kimura, Emi Akizuki, Toshihiko Nishidate, Kenji Okita, Takayuki Nobuoka, Toru Mizuguchi, Koichi Hirata, Ichiro Takemasa

Clinical and experimental gastroenterology 13 577 - 587 2020年12月 [国際誌]

Introduction: Delayed gastric emptying (DGE) remains an important problem after pancreaticoduodenectomy (PD). There is a lack of effective treatments for early recovery of oral dietary intake. Rikkunshito (RKT), a Japanese herbal medicine, has been gaining attention as a facilitator of gastric emptying. We evaluated the effects of RKT on DGE after PD. Methods: In this prospective, randomized, open-labeled study, patients were randomly allocated before PD in a 1:1 ratio to the RKT group or the control group that received no additional treatment. The RKT group received 2.5 g of RKT three times daily (7.5 g/day) from postoperative day (POD) 1 to POD 21. The primary endpoint was the incidence of DGE. Secondary endpoints were short-term postoperative outcomes including oral dietary intake volume and perioperative changes in levels of the hormones ghrelin and leptin. Patients were observed until hospital discharge. Results: Twenty-six patients in each group (n = 52) completed the protocol treatment and were included in the analysis set. There were no statistically significant differences in basic characteristics and operative factors. The overall incidence of DGE was not statistically different between the RKT and control groups (30.8% vs 30.8%, p>0.9999). There were no statistically significant differences in the amount of postoperative oral dietary intake represented by total dietary intake (TDI) up to POD 14 and POD 21, complications, and length of hospital stay. No adverse events related to this study were observed. In the RKT group, total ghrelin and acyl-ghrelin were significantly upregulated and leptin was significantly downregulated earlier than in the control group. Conclusion: RKT treatment from POD 1 to 21 did not reduce the incidence of DGE and had no clinically beneficial effect on short-term postoperative outcomes irrespective of changes in hormone levels.

DOI PubMed

The Unique Mental Impacts of Breast-Conserving Surgery and Mastectomy According to a Multi-Centered Cross Sectional Survey Conducted in Japan

Yuri Hazawa, Goro Kutomi, Hiroaki Shima, Toshio Honma, Tosei Ohmura, Asaka Wada, Toshihiko Mikami, Miki Hotta, Momoka Narumi, Tomohiro Ishinuki, Yoshika Kuno, Makoto Meguro, Ichiro Takemasa, Minoru Okazaki, Hideji Masuoka, Kazuaki Asaishi, Toshio Ohyanagi, Thomas T. Hui, Toru Mizuguchi

Archives of Breast Cancer ( Archives of Breast Cancer ) 119 - 126 2020年08月

Background: Improving health-related quality of life (HRQOL) has become a fundamental goal of breast cancer management. This study aimed to examine the differences between the QOL outcomes of breast-conserving surgery (BCS) and mastectomy. We also established structural equation models for BCS and mastectomy to elucidate their unique effects on QOL.Methods: Between July 2019 and November 2019, 254 patients, who were scheduled to visit one of four clinics, were recruited for this study. We evaluated HRQOL using various questionnaires, such as the BREAST-Q, EQ-5D-5L, and Hospital Anxiety and Depression Scale (HADS). The relationships among the examined clinical indicators were evaluated using structural equation modeling (SEM). Results: The QOL scores of the BCS group were better than those of the mastectomy group (0.85±0.129 vs. 0.81±0.12, P=0.020). Also, anxiety (2.94±2.95 vs. 3.81±3.08, P=0.025) and depression (2.55±2.77 vs. 3.74±3.19, P=0.002) were less severe in the BCS group than in the mastectomy group. Furthermore, the relationships among QOL status and mental health status were more complex in the BCS group than in the mastectomy group (Chi-square minimization p-value: 0.231 vs. 0.469, respectively). Also, depression directly affected QOL in the mastectomy group (R=-0.47), but not in the BCS group.Conclusions: There were differences in QOL and mental health between the BCS and mastectomy groups. SEM is useful for identifying such differences, which can be used to develop strategies for improving QOL.

DOI

【外科栄養-最新のアプローチ】肝臓外科手術の周術期栄養管理

水口徹, 永山稔, 山口洋志, 石貫智裕, 久野芳佳, 今村将史, 竹政伊知朗, 木村康利

外科 ( (株)南江堂 ) 82 ( 4 ) 357 - 363 2020年04月

＜文献概要＞肝切除術周術期における栄養介入について,新たなメタ解析を追加し概説する.ERAS推奨のガイドラインでは,対象患者に術前7日間の栄養介入がすすめられている.免疫調整栄養剤は周術期の全合併症を減少させ(p<0.001),在院日数を短縮する(p=0.007).BCAA製剤も全合併症を低下させる(p=0.03).ERAS導入は周術期の全合併症を減少させる(p<0.001).技術的な課題解決に加えて,肝切除術周術期の栄養介入は臨床成績を改善させる可能性がある.

Self‐Renewal Capability of Hepatocytic Parental Progenitor Cells Derived From Adult Rat Liver Is Maintained Long Term When Cultured on Laminin 111 in Serum‐Free Medium

Junichi Kino, Norihisa Ichinohe, Masayuki Ishii, Hiromu Suzuki, Toru Mizuguchi, Naoki Tanimizu, Toshihiro Mitaka

Hepatology Communications ( Wiley ) 4 ( 1 ) 21 - 37 2020年01月

DOI

Central pancreatectomy in portal annular pancreas for metastatic renal cell carcinoma: a case report

Hiroshi Yamaguchi, Yasutoshi Kimura, Minoru Nagayama, Masafumi Imamura, Shingo Tanaka, Makoto Yoshida, Eiji Yoshida, Hiroki Fujino, Takashi Machiki, Koji Miyanishi, Toru Mizuguchi, Junji Kato, Ichiro Takemasa

World Journal of Surgical Oncology ( Springer Science and Business Media LLC ) 17 ( 1 ) 2019年12月

DOI

Immunohistological analysis of pancreatic carcinoma after vaccination with survivin 2B peptide: Analysis of an autopsy series.

Terufumi Kubo, Giichiro Tsurita, Yoshihiko Hirohashi, Hiroshi Yasui, Yasunori Ota, Kazue Watanabe, Aiko Murai, Kazuhiko Matsuo, Hiroko Asanuma, Hiroaki Shima, Satoshi Wada, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Toru Mizuguchi, Koichi Hirata, Ichiro Takemasa, Kohzoh Imai, Noriyuki Sato, Toshihiko Torigoe

Cancer science 110 ( 8 ) 2386 - 2395 2019年08月 [国際誌]

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer by providing new options in addition to existing therapies. However, peptide vaccination therapies still represent an attractive approach, because of the antigen specificity. We identified survivin 2B peptide (SVN-2B), a 9-mer antigenic peptide encoded by survivin, and an SVN-2B peptide vaccine-based phase II randomized clinical trial targeting unresectable and refractory pancreatic carcinoma was undertaken. The SVN-2B peptide vaccine did not have any statistically significant clinical benefits in that study. Therefore, we undertook an autopsy study to analyze the immune status of the pancreatic cancer lesions at the histological level. Autopsies were carried out in 13 patients who had died of pancreatic cancer, including 7 who had received SVN-2B peptide vaccination and 6 who had not, as negative controls. The expression of immune-related molecules was analyzed by immunohistochemical staining. Cytotoxic T lymphocytes were analyzed by tetramer staining and enzyme-linked immunospot assay. Histological analysis revealed dense infiltration of CD8+ T cells in some lesions in patients who had received the SVN-2B peptide vaccine. A high rate of programmed cell death ligand 1 expression in cancer cells was observed in these cases, indicating that CTLs were induced by SVN-2B peptide vaccination and had infiltrated the lesions. The lack of a significant antitumor effect was most likely attributable to the expression of immune checkpoint molecules. These findings suggest that the combination of a tumor-specific peptide vaccine and an ICI might be a promising approach to the treatment of pancreatic carcinoma in the future.

DOI PubMed

Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA-A24-positive pancreatic adenocarcinoma

Hiroaki Shima, Giichiro Tsurita, Satoshi Wada, Yoshihiko Hirohashi, Hiroshi Yasui, Hiroshi Hayashi, Takashi Miyakoshi, Kazue Watanabe, Aiko Murai, Hiroko Asanuma, Serina Tokita, Terufumi Kubo, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Yutaka Nakae, Osamu Sugita, Yoichi M. Ito, Yasunori Ota, Yasutoshi Kimura, Goro Kutomi, Koichi Hirata, Toru Mizuguchi, Kohzoh Imai, Ichiro Takemasa, Noriyuki Sato, Toshihiko Torigoe

CANCER SCIENCE ( WILEY ) 110 ( 8 ) 2378 - 2385 2019年08月

The prognosis of advanced pancreatic adenocarcinoma is still extremely poor. This study sought to determine the efficacy of, and immunological response to, peptide vaccination therapy in patients with this disease. In this multicenter randomized phase II study, patients with advanced pancreatic adenocarcinoma after gemcitabine and/or tegafur/gimeracil/oteracil were randomly assigned to 3 groups that each received a 2-step treatment course. In Step 1, the groups received treatments of: (i) survivin 2B peptide (SVN-2B) plus interferon-beta (IFN beta); (ii) SVN-2B only; or (iii) placebo until the patients show progression. In Step 2, all patients who consented to participate received 4 treatments with SVN-2B plus IFN beta. The primary endpoint was progression-free survival (PFS) after initiation of Step 1 treatment. Secondary endpoints included immunological effects assessed by analysis of PBMCs after Step 1. Eighty-three patients were randomly assigned to receive SVN-2B plus IFN beta (n = 30), SVN-2B (n = 34), or placebo (n = 19). No significant improvement in PFS was observed. Survivin 2B-specific CTLs were found to be increased in the SVN-2B plus IFN beta group by tetramer assay. Among patients who participated in Step 2, those who had received SVN-2B plus IFN beta in Step 1 showed better overall survival compared with those who had received placebo in Step 1. Patients vaccinated with SVN-2B plus IFN beta did not have improved PFS, but showed significant immunological reaction after vaccination. Subgroup analysis suggested that a longer SVN-2B plus IFN beta vaccination protocol might confer survival benefit. (Clinical trial registration number: UMIN 000012146).

DOI

Scoring criteria for determining the safety of liver resection for malignant liver tumors

Harada K, Nagayama M, Ohashi Y, Chiba A, Numasawa K, Meguro M, Kimura Y, Yamaguchi H, Kobayashi M, Miyanishi K, Kato J, Mizuguchi T

World J Meta-Anal ( Baishideng Publishing Group Inc. ) 7 ( 5 ) 234 - 248 2019年05月 [査読有り]

DOI

Case report: Long-term survival of a pancreatic cancer patient immunized with an SVN-2B peptide vaccine.

Hiroaki Shima, Goro Kutomi, Fukino Satomi, Masafumi Imamura, Yasutoshi Kimura, Toru Mizuguchi, Kazue Watanabe, Akari Takahashi, Aiko Murai, Tomohide Tsukahara, Takayuki Kanaseki, Yoshihiko Hirohashi, Yuji Iwayama, Tetsuhiro Tsuruma, Hidekazu Kameshima, Noriyuki Sato, Toshihiko Torigoe, Ichiro Takemasa

Cancer immunology, immunotherapy : CII 67 ( 10 ) 1603 - 1609 2018年10月 [国際誌]

A 62-year-old woman who underwent surgery to treat pancreatic cancer provided written, informed consent to undergo adjuvant therapy with gemcitabine, tegafur, and uracil. However, this was stopped after only 14 days due to Grade 4 neutropenia. She was then started on vaccine therapy with Survivin 2B peptide (SVN-2B) including IFA and INF-α. Although metastatic lung tumors were identified and resected at 82 months after surgery, the patient has remained free of new or relapsed disease for 12 years thereafter. Tetramer and ELISPOT assays revealed the continuous circulation of SVN-2B-restricted cytotoxic T-lymphocytes (CTLs) in her peripheral blood, and CTL clones had specific activity for SVN-2B at 12 years after surgery. The adverse effects of the peptide vaccination were tolerable and comprised low-grade headache, nausea, and fatigue. A prognosis beyond 10 years in the face of pancreatic cancer with distant metastasis is extremely rare. This experience might indicate the value of cancer vaccination therapy.

DOI PubMed

外科医のための癌免疫療法進行膵臓がんを対象とした複合型CTLワクチン療法第2相試験

水口徹, 島宏彰, 九冨五郎, 木村康利, 竹政伊知朗, 鳥越俊彦, 廣橋良彦, 塚原智英, 金関貴幸, 釣田義一郎, 安井寛, 和田聡, 林宏至, 宮腰崇

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 78 ( 増刊 ) 419 - 419 2017年10月

Hepatocytic parental progenitor cells of rat small hepatocytes maintain self-renewal capability after long-term culture

Masayuki Ishii, Junichi Kino, Norihisa Ichinohe, Naoki Tanimizu, Takafumi Ninomiya, Hiromu Suzuki, Toru Mizuguchi, Koichi Hirata, Toshihiro Mitaka

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP ) 7 46177 2017年04月 [査読有り]

The liver has a variety of functions for maintaining homeostasis, and hepatocytes play a major role. In contrast with the high regenerative capacity of mature hepatocytes (MHs) in vivo, they have not been successfully expanded ex vivo. Here we demonstrate that CD44-positive cells sorted from small hepatocyte (SH) colonies derived from a healthy adult rat liver can proliferate on a Matrigel-coated dish in serum-free chemically defined medium; in addition, a subpopulation of the cells can divide more than 50 times in a period of 17 weeks every 4-week-passage. The passage cells retained the capability to recover highly differentiated functions, such as glycogen storage, CYP activity and bile secretion. When Matrigel-treated cells from the third passage were transplanted into retrorsine/partial hepatectomytreated rat livers, the cells engrafted to differentiate into MHs and cholangiocytes. These results suggest that long-term cultured CD44(+) SHs retain hepatocytic characteristics in vitro and the capability to differentiate into hepatocytes and cholangiocytes in vivo. Thus, a newly identified subpopulation of MHs possessing the attributes of hepatocytic stem/progenitor cells can be passaged several times without losing hepatocytic characteristics.

DOI PubMed

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

Norihisa Ichinohe, Masayuki Ishii, Naoki Tanimizu, Junko Kon, Yusuke Yoshioka, Takahiro Ochiya, Toru Mizuguchi, Koichi Hirata, Toshihiro Mitaka

STEM CELLS ( WILEY ) 35 ( 4 ) 920 - 931 2017年04月 [査読有り]

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.

DOI PubMed

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