研究者詳細 - 鈴木　拓

論文 - 鈴木　拓

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Cribriform-type adenocarcinoma of the colorectum: comprehensive molecular analyses of a distinctive histologic subtype of colorectal cancer.

Shun Yamada, Mitsumasa Osakabe, Makoto Eizuka, Mai Hashimoto, Noriyuki Uesugi, Naoki Yanagawa, Koki Otsuka, Hiromu Suzuki, Takayuki Matsumoto, Tamotsu Sugai

Carcinogenesis 43 ( 6 ) 601 - 610 2022年06月 [国際誌]

Colorectal adenocarcinoma (CRA) is characterized by marked heterogeneity and may be composed of an admixture of various histologic patterns, including well-formed gland and cribriform types. Although tumors displaying a prominent or predominant cribriform feature are frequently found in CRA, this type may contain specific histologic variants with a characteristic molecular alteration. We investigated the molecular features of 51 primary CRAs with a predominant cribriform histology using array-based analyses [somatic copy number alterations (SCNAs); mRNA expression]. Mutations (TP53, KRAS, PIK3CA and BRAF) and DNA methylation status were also analyzed. The crypt isolation method was used to obtain isolated tumor glands of each type separately. All patients were classified by their CRA histologic subtype into two groups: well-formed gland and cribriform. Next, we performed cluster analysis to stratify SCNA and mRNA expression patterns between the two subtypes. Two distinctive subgroups were stratified based on patterns of SCNA and mRNA expression and were correlated with each histologic subtype. The cribriform type was characterized by a high frequency of SCNA compared with that of the well-formed gland type and was closely associated with the expression of specific mRNAs. In addition, the frequency of KRAS mutation was significantly higher in the cribriform type than in the well-formed gland type. Finally, there was no difference in DNA methylation status between the two subtypes. Overall, these data suggest that the cribriform type provides important insights into colorectal carcinogenesis, suggesting specific potential histologic implications based on the molecular profile.

DOI PubMed

Comprehensive Analysis of microRNA Expression During the Progression of Colorectal Tumors.

Tamotsu Sugai, Ryo Sugimoto, Makoto Eizuka, Mitsumasa Osakabe, Shun Yamada, Naoki Yanagawa, Takayuki Matsumoto, Hiromu Suzuki

Digestive diseases and sciences 68 ( 3 ) 813 - 823 2022年06月 [国際誌]

BACKGROUND: No effective early diagnostic biomarkers are available for colorectal cancer (CRC). Therefore, we sought to identify new biomarkers that could identify CRC from progression as a pre-cancerous lesion to its invasive form. Recent studies have shown that microRNAs (miRs) are associated with the onset of cancer invasion and progression. AIMS: We hypothesized that the identification of miRs associated with CRC might be useful to detect this disease at early stages. METHODS: We conducted an integrated analysis of 79 isolated colorectal tumor glands, including adenomas, intramucosal cancers, and invasive CRCs that showed a microsatellite stable phenotype using GeneChip miRNA 4.0 microarray assays. The colorectal tumors we examined were divided into 2 cohorts (42 in the first cohort and 37 in the second cohort). RESULTS: First, cluster analysis was performed to stratify expression patterns of multiple miRs that were pooled according to the following criteria: fold change in expression (< -2.0 or > 2.0), p < 0.05, and mature miRs. As a result, the expression patterns of pooled miRs were subdivided into 3 subgroups that were correlated with tumor grade. Each subgroup was characterized by specific miRs. In addition, we found that specific miRs, including miR-140-3p and miR-378i, were closely associated with cancer invasion. Finally, we analyzed paired dysregulated miRs between adenomatous and cancerous components present within the same tumor. DISCUSSION: We showed that several miRs were dysregulated during progression from adenoma to intramucosal cancer. Specific miRs may have key roles in progression from intramucosal tumor to invasive CRC.

DOI PubMed

大腸癌および癌近傍正常粘膜のmessenger RNAとmicro RNAの網羅的解析

伊藤勇馬, 刑部光正, 杉本亮, 柳川直樹, 大塚幸喜, 佐々木章, 松本主之, 鈴木拓, 菅井有

日本病理学会会誌 ( (一社)日本病理学会 ) 111 ( 1 ) 312 - 312 2022年03月

病態解明による大腸腫瘍診療の新展開早期大腸がん浸潤先進部の分子解析による新規バイオマーカー・治療標的の探索

須藤豪太, 鈴木拓, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 119 ( 臨増総会 ) A104 - A104 2022年03月

Relevance of gene mutations and methylation to the growth of pancreatic intraductal papillary mucinous neoplasms based on pyrosequencing.

Go Asano, Katsuyuki Miyabe, Hiroyuki Kato, Michihiro Yoshida, Takeshi Sawada, Yasuyuki Okamoto, Hidenori Sahashi, Naoki Atsuta, Kenta Kachi, Akihisa Kato, Naruomi Jinno, Makoto Natsume, Yasuki Hori, Itaru Naitoh, Kazuki Hayashi, Yoichi Matsuo, Satoru Takahashi, Hiromu Suzuki, Hiromi Kataoka

Scientific reports 12 ( 1 ) 419 - 419 2022年01月 [国際誌]

We aimed to assess some of the potential genetic pathways for cancer development from non-malignant intraductal papillary mucinous neoplasm (IPMN) by evaluating genetic mutations and methylation. In total, 46 dissected regions in 33 IPMN cases were analyzed and compared between malignant-potential and benign cases, or between malignant-potential and benign tissue dissected regions including low-grade IPMN dissected regions accompanied by malignant-potential regions. Several gene mutations, gene methylations, and proteins were assessed by pyrosequencing and immunohistochemical analysis. RASSF1A methylation was more frequent in malignant-potential dissected regions (p = 0.0329). LINE-1 methylation was inversely correlated with GNAS mutation (r = - 0.3739, p = 0.0105). In cases with malignant-potential dissected regions, GNAS mutation was associated with less frequent perivascular invasion (p = 0.0128), perineural invasion (p = 0.0377), and lymph node metastasis (p = 0.0377) but significantly longer overall survival, compared to malignant-potential cases without GNAS mutation (p = 0.0419). The presence of concordant KRAS and GNAS mutations in the malignant-potential and benign dissected regions were more frequent among branch-duct IPMN cases than among the other types (p = 0.0319). Methylation of RASSF1A, CDKN2A, and LINE-1 and GNAS mutation may be relevant to cancer development, IPMN subtypes, and cancer prognosis.

DOI PubMed

Genome-Wide Analysis of microRNA and mRNA Expression in Colorectal Intramucosal Neoplasia and Colorectal Cancer With a Microsatellite-Stable Phenotype Based on Adenoma-Carcinoma Sequences.

Tamotsu Sugai, Mitsumasa Osakabe, Takeshi Niinuma, Ryo Sugimoto, Makoto Eizuka, Yoshihito Tanaka, Naoki Yanagawa, Koki Otsuka, Akira Sasaki, Takayuki Matsumoto, Hiromu Suzuki

Frontiers in oncology 12 831100 - 831100 2022年 [国際誌]

Background: Although MicroRNAs (miRNAs) play important roles in various biological processes, the biological functions of miRNAs are achieved through mRNAs. The aim of this study is to identify dysregulated miRNA/mRNA expression patterns in colorectal tumors. Methods: We examined 42 colorectal tumors [15 adenomas, 8 intramucosal cancers (IMCs), and 19 invasive colorectal cancers (CRCs)] with the microsatellite stable (MSS) phenotype (first cohort). The first cohort was used for genome-wide miRNA and mRNA expression arrays, whereas the second cohort (37 colorectal neoplasias) was used for validation analyses. Finally, we used 15 cases of "adenoma in/with carcinoma" to identify network patterns of miRNAs/mRNAs that were directly associated with neoplastic progression. In addition, simple regression analysis for array-based and RT-PCR analyses was performed to select candidate miRNA-mRNA pairs. Transfection of miRNA mimics was also performed to confirm whether target mRNA expression is affected by specific miRNAs. Results: Specific paired miRNA/mRNA networks, including hsa-miR-34a-5p/SLC12A2, hsa-miR-15b-5p/SLC12A2, hsa-miR-195-5p/SLC12A2, hsa-miRNA-502-3p/OLFM4, hsa-miRNA-6807-5p/ZG16, and hsa-miRNA 3064-5p/SH3BGRL3, were identified in samples of adenoma, IMC, and CRC with the MSS phenotype. In adenomatous lesions obtained from the same tumor with a carcinomatous lesion, we identified pairs of miRNA-130a-3p/HSPA8 and miRNA-22-3p/RP53 that were linked to multiple pathways. On the other hand, 2 pairs of miRNA/mRNA (miRNA-660-5p and miRNA-664a-5p/APP) were found in isolated carcinomatous glands. Ectopic expression of miRNA 3064-5p suppressed SH3BGRL3 expression. Conclusions: We found that networks based on specific pairs of miRNAs/mRNAs contribute to progression from adenomatous and carcinomatous lesions. Our results provide insights into the molecular tumorigenesis of colorectal tumors.

DOI PubMed

Comprehensive analyses of microRNA and mRNA expression in colorectal serrated lesions and colorectal cancer with a MSI phenotype.

Tamotsu Sugai, Mitsumasa Osakabe, Takeshi Niinuma, Makoto Eizuka, Yoshihito Tanaka, Shun Yamada, Naoki Yanagawa, Koki Otsuka, Akira Sasaki, Takayuki Matsumoto, Hiromu Suzuki

Genes, chromosomes & cancer 61 ( 3 ) 161 - 171 2021年11月 [国際誌]

MicroRNA (miRNA) expression is dysregulated in human tumors, thereby contributing to tumorigenesis through altered expression of mRNA. Thus, identification of the relationships between miRNAs and mRNAs is important for evaluating the molecular mechanisms of tumors. Additionally, elucidation of the molecular features of serrated lesions is essential in colorectal tumorigenesis. Here, we examined the relationships of miRNA and mRNA expressed in serrated lesions, including 26 sessile serrated lesions (SSLs), 12 traditional serrated adenomas (TSAs), and 11 colorectal cancers (CRCs) with a microsatellite instability (MSI) phenotype using crypt isolation. We divided the samples into the first and second cohorts for validation. Array-based expression analyses were used to evaluate miRNAs and mRNAs with opposite expression patterns in isolated tumor glands. In addition, we validated the relationships of miRNA/mRNA pairs in the second cohort using real-time polymerase chain reaction. We found that the expression of miRNA-5787 was correlated with reciprocal expression of 2 mRNAs, i.e., SRRM2 and POLR2J3, in SSL samples. In TSA samples, 2 pairs of miRNAs/mRNAs showing opposite expression patterns, i.e., miRNA-182-5p/ETF1 and miRNA-200b-3p/MYB, were identified. Ultimately, three pairs of miRNAs/mRNAs with opposite expression patterns, including miRNA-222-3p/SLC26A3, miRNA-6753-3p/FABP1, and miRNA-222-3p/OLFM4, were retained in CRC with an MSI phenotype. Finally, we performed transfection with an miR-222-3p mimic to confirm the expression of SLC26A3 and OLFM4; the results showed that ectopic expression of miR-222-3p moderately suppressed OLFM4 and downregulated SLC26A3 to some extent. Overall, our results provided basic insights into the evaluation of colorectal tumorigenesis of serrated lesions and CRC with an MSI phenotype. This article is protected by copyright. All rights reserved.

DOI PubMed

DLEU1 promotes oral squamous cell carcinoma progression by activating interferon-stimulated genes.

Yui Hatanaka, Takeshi Niinuma, Hiroshi Kitajima, Koyo Nishiyama, Reo Maruyama, Kazuya Ishiguro, Mutsumi Toyota, Eiichiro Yamamoto, Masahiro Kai, Akira Yorozu, Shohei Sekiguchi, Kazuhiro Ogi, Hironari Dehari, Masashi Idogawa, Yasushi Sasaki, Takashi Tokino, Akihiro Miyazaki, Hiromu Suzuki

Scientific reports 11 ( 1 ) 20438 - 20438 2021年10月 [国際誌]

Long noncoding RNAs (lncRNAs) are deeply involved in cancer development. We previously reported that DLEU1 (deleted in lymphocytic leukemia 1) is one of the lncRNAs overexpressed in oral squamous cell carcinoma (OSCC) cells, where it exhibits oncogenic activity. In the present study, we further clarified the molecular function of DLEU1 in the pathogenesis of OSCC. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that DLEU1 knockdown induced significant changes in the levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27 acetylation (H3K27ac) in OSCC cells. Notably, DLEU1 knockdown suppressed levels of H3K4me3/ H3K27ac and expression of a number of interferon-stimulated genes (ISGs), including IFIT1, IFI6 and OAS1, while ectopic DLEU1 expression activated these genes. Western blot analysis and reporter assays suggested that DLEU1 upregulates ISGs through activation of JAK-STAT signaling in OSCC cells. Moreover, IFITM1, one of the ISGs induced by DLUE1, was frequently overexpressed in primary OSCC tumors, and its knockdown inhibited OSCC cell proliferation, migration and invasion. These findings suggest that DLEU1 exerts its oncogenic effects, at least in part, through activation of a series ISGs in OSCC cells.

DOI PubMed

大腸癌の腫瘍近傍分離正常腺管と分離癌腺管におけるmiRNA/mRNA発現状態の網羅的解析

刑部光正, 伊藤勇馬, 杉本亮, 上杉憲幸, 柳川直樹, 鈴木拓, 菅井有

日本癌学会総会記事 ( (一社)日本癌学会 ) 80回 [P14 - 3] 2021年09月

内視鏡診療で目指す大腸腫瘍性病変に対するTranslational researchの確立

三宅高和, 吉井新二, 鈴木拓, 山野泰穂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 129回・123回 26 - 26 2021年09月

活性化マクロファージはIL-1β-SAA1 axisを介して早期大腸がんの浸潤を促進する

須藤豪太, 山本英一郎, 青木敬則, 高澤啓, 新沼猛, 久保俊之, 萬顕, 吉戸文乃, 北嶋洋志, 甲斐正広, 小山内誠, 仲瀬裕志, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 80回 [P14 - 3] 2021年09月

Helicobacter pylori除菌後胃がんと背景胃粘膜におけるDNAメチローム解析

山本英一郎, 吉戸文乃, 須藤豪太, 三橋慧, 北嶋洋志, 新沼猛, 甲斐正広, 原田拓, 佐々木基, 久保俊之, 山野泰穂, 仲瀬裕志, 菅井有, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 80回 [P14 - 5] 2021年09月

エピジェネティクス阻害剤のGIST細胞におけるエピゲノム修飾、遺伝子発現への影響の統合解析

吉戸文乃, 須藤豪太, 北嶋洋志, 新沼猛, 甲斐正広, 原田拓, 佐々木基, 久保俊之, 仲瀬裕志, 菅井有, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 80回 [P14 - 7] 2021年09月

頭頸部扁平上皮がんの腫瘍微小環境におけるAEBP1の解析

関口翔平, 萬顕, 山本英一郎, 新沼猛, 高澤啓, 須藤豪太, 小池和茂, 畠中柚衣, 吉戸文乃, 北嶋洋志, 甲斐正広, 小山内誠, 高野賢一, 宮崎晃亘, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 80回 [J14 - 5] 2021年09月

Regulatory roles of claudin-1 in cell adhesion and microvilli formation.

Kumi Takasawa, Akira Takasawa, Taishi Akimoto, Kazufumi Magara, Tomoyuki Aoyama, Hiroshi Kitajima, Taro Murakami, Yusuke Ono, Daisuke Kyuno, Hiromu Suzuki, Makoto Osanai

Biochemical and biophysical research communications 565 36 - 42 2021年08月 [国際誌]

Aberrant expression of tight junction proteins has recently been focused on in the cancer research field. We previously showed that claudin-1 is aberrantly expressed from an early stage of uterine cervical adenocarcinoma and contributes to malignant potentials. To elucidate the molecular mechanisms underlying tumor-promoting roles of claudin-1, we established and analyzed claudin-1 knockout cells. Knockout of claudin-1 suppressed conventional tight junctional functions, barrier and fence functions, and expression of cell adhesion-associated proteins including E-cadherin. Comparative proteome analysis revealed that expression of claudin-1 affected expression of a wide range of proteins, especially proteins that are associated with cell adhesion and actin cytoskeleton remodeling. Interactome analysis of the identified proteins revealed that E-cadherin and focal adhesion kinase play central roles in the claudin-1-dependently affected protein network. Moreover, knockout of claudin-1 significantly suppressed microvilli formation and activity of Ezrin/Radixin/Moesin. Taken together, the results indicate that expression of claudin-1 affects not only conventional tight junction function but also expression and activity of a wide range of proteins, especially proteins that are associated with cell adhesion and actin cytoskeleton remodeling, to contribute to malignant potentials and microvilli formation in cervical adenocarcinoma cells.

DOI PubMed

Activated macrophages promote invasion by early colorectal cancer via an IL-1β-SAA1 axis.

Gota Sudo, Hironori Aoki, Eiichiro Yamamoto, Akira Takasawa, Takeshi Niinuma, Ayano Yoshido, Hiroshi Kitajima, Akira Yorozu, Toshiyuki Kubo, Taku Harada, Kazuya Ishiguro, Masahiro Kai, Akio Katanuma, Hiro-O Yamano, Makoto Osanai, Hiroshi Nakase, Hiromu Suzuki

Cancer science 112 ( 10 ) 4151 - 4165 2021年07月 [国際誌]

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA-sequencing (RNA-seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues, and detected significant upregulation of SAA1 in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Co-culture experiments using CRC cell lines and THP-1 cells suggested that interleukin 1β (IL-1β) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL-1β. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1-like/M2-like macrophages at SAA1-positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of MMP-9 in macrophages. Our data suggest that tumor-associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1, and that SAA1 may be a predictive biomarker and a useful therapeutic target.

DOI PubMed

A genome-wide analysis of the molecular alterations occurring in the adenomatous and carcinomatous components of the same tumor based on the adenoma-carcinoma sequence.

Tamotsu Sugai, Mitsumasa Osakabe, Wataru Habano, Yoshihito Tanaka, Makoto Eizuka, Ryo Sugimoto, Naoki Yanagawa, Takayuki Matsumoto, Hiromu Suzuki

Pathology international 71 ( 9 ) 582 - 593 2021年07月 [国際誌]

Identification of molecular alterations occurring in the adenomatous and carcinomatous components within the same tumor would greatly enhance understanding of the neoplastic progression of colorectal cancer. We examined somatic copy number alterations (SCNAs) and mRNA expression at the corresponding loci involved in the adenoma-carcinoma sequence in the isolated adenomatous and cancer glands of the same tumor in 15 cases of microsatellite-stable "carcinoma in adenoma," using genome-wide SNP and global gene expression arrays. Multiple copy-neutral loss of heterozygosity events were detected at 4q13.2, 15q15.1, and 14q24.3 in the adenomatous component and at 4q13.2, 15q15.1, and 14q24.3 in the carcinomatous component. There were significant differences in the copy number (CN) gain frequencies at 20q11.21-q13.33, 8q13.3, 8p23.1, and 8q21.2-q22.2 between the adenomatous and carcinomatous components. Finally, we found a high frequency of five genotypes involving CN gain with upregulated expression of the corresponding gene (RPS21, MIR3654, RSP20, SNORD54, or ASPH) in the carcinomatous component, whereas none of these genotypes were detected in the adenomatous component. This finding is interesting in that CN gain with upregulated gene expression may enhance gene function and play a crucial role in the progression of an adenoma into a carcinomatous lesion.

DOI PubMed

Immunohistochemical Examination is Highly Sensitive and Specific for Detection of the V600E BRAF Mutation in Colorectal Serrated Lesions.

Noriyuki Yamada, Makoto Eizuka, Ryo Sugimoto, Yoshihito Tanaka, Naoki Yanagawa, Hiroo Yamano, Hiromu Suzuki, Takayuki Matsumoto, Tamotsu Sugai

Applied immunohistochemistry & molecular morphology : AIMM 29 ( 6 ) 446 - 453 2021年07月 [国際誌]

Mutations in BRAF are important events in colorectal serrated lesions and specific genetic markers for the serrated pathway. However, examination of BRAF mutations is not easy in routine histopathologic analyses. Here, the authors examined 73 colorectal serrated lesions, including 21 hyperplastic polyps, 32 traditional serrated adenomas, and 30 sessile serrated lesions, for comparison of BRAF mutation status with immunopositive expression of the anti-BRAF V600E mutation-specific antibody VE1. Thirty-two tubular adenomas (TAs) were examined as controls. In addition, 5 examples of sessile serrated lesion with dysplasia were included. Mutations in BRAF (exon 15; V600E) and KRAS (exon 2) were analyzed in serrated lesions and TAs using pyrosequencing. Finally, the authors compared BRAF mutations with immunohistochemical expression of VE1 antibodies against the BRAF V600E mutation, which was examined based on quantitative analyses and correlations between semiquantitative (0, 1+, or 2+) and quantitative results in colorectal serrated lesions. The cut-off value of VE1 expression (32%) was set based on receiver operating characteristic curve analysis. In the current study, mutations in BRAF were well correlated with VE1 expression in serrated lesions, although no TAs without BRAF mutations were immunopositive. In contrast, serrated lesions and TAs with mutations in KRAS were not stained for VE1 expression. In serrated lesions, although the sensitivity was 96.2% to 100%, the specificity was 90.0% to 100%. In addition, there was also good correlation between semiquantitative and quantitative results. Analysis of BRAF V600E expression may be pathologically useful, particularly in routine histopathologic diagnosis.

DOI PubMed

An Integrated Epigenome and Transcriptome Analysis to Clarify the Effect of Epigenetic Inhibitors on GIST.

Takeshi Niinuma, Hiroshi Kitajima, Eiichiro Yamamoto, Reo Maruyama, Hironori Aoki, Taku Harada, Kazuya Ishiguro, Gota Sudo, Mutsumi Toyota, Ayano Yoshido, Masahiro Kai, Hiroshi Nakase, Tamotsu Sugai, Hiromu Suzuki

Anticancer research 41 ( 6 ) 2817 - 2828 2021年06月 [国際誌]

BACKGROUND/AIM: Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain further insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells. MATERIALS AND METHODS: To reverse epigenetic silencing, GIST-T1 cells were treated with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, and subsequently H3K4me3 levels, the DNA methylome, and the transcriptome were analyzed. RESULTS: Treatment with epigenetic inhibitors not only up-regulated genes with DNA methylation, but also genes related to interferon signaling. ChIP-seq analysis revealed that drug treatment up-regulated H3K4me3 levels in retrotransposons, including endogenous retroviruses (ERV). Finally, utilizing the omics data, we found that hypermethylation of MEG3 is a frequent event and an indicator of poorer prognosis in GIST patients. CONCLUSION: Epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. Moreover, epigenome data could be a useful resource to identify novel GIST-related genes.

DOI PubMed

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

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