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Keiji Nakasho - One of the best experts on this subject based on the ideXlab platform.
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transdifferentiation into biliary Ductular Cells of hepatocytes transplanted into the spleen
Pathology, 2008Co-Authors: Hirofumi Watanabe, Masaki Hata, Nobuyuki Terada, Haruyasu Ueda, Naoko Yamada, Koji Yamanegi, Hideki Ohyama, Michiko Kakihana, Haruki Okamura, Keiji NakashoAbstract:Summary Aims Transplantation of rat hepatocytes into the syngeneic rat spleen results in the appearance of cytokeratin (CK)7 and CK19 positive biliary Cells that form ductules. We examined whether hepatocytes are the origin of these biliary Ductular Cells. Methods We transplanted rat dipeptidyl peptidase IV (DPPIV) positive hepatocytes into the liver of retrorsinetreated and partially hepatectomised DPPIV negative rats, which resulted in proliferation of DPPIV positive hepatocytes in the liver. Two months later, hepatocytes were prepared from chimaeric livers of these rats and transplanted into the spleen of DPPIV negative rats. Four weeks later, the expression of DPPIV in CK7 positive ductules in the spleen was examined by immunofluorescent double-staining. Results In the spleen of DPPIV negative rats transplanted with hepatocytes prepared from the chimaeric livers, DPPIV was found to be expressed in some CK7 positive biliary ductules where only a fraction of Cells expressed DPPIV, whereas in the spleen of DPPIV negative rats transplanted with hepatocytes from livers of DPPIV positive rats, DPPIV was expressed in all CK7 positive biliary ductules. Conclusion The present study indicates that hepatocytes transplanted into the spleen could transdifferentiate into biliary Cells that aggregate to form Ductular structures.
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Transdifferentiation into biliary Ductular Cells of hepatocytes transplanted into the spleen
Pathology, 2008Co-Authors: Hirofumi Watanabe, Masaki Hata, Nobuyuki Terada, Haruyasu Ueda, Naoko Yamada, Koji Yamanegi, Hideki Ohyama, Michiko Kakihana, Haruki Okamura, Keiji NakashoAbstract:Transplantation of rat hepatocytes into the syngeneic rat spleen results in the appearance of cytokeratin (CK)7 and CK19 positive biliary Cells that form ductules. We examined whether hepatocytes are the origin of these biliary Ductular Cells. We transplanted rat dipeptidyl peptidase IV (DPPIV) positive hepatocytes into the liver of retrorsine-treated and partially hepatectomised DPPIV negative rats, which resulted in proliferation of DPPIV positive hepatocytes in the liver. Two months later, hepatocytes were prepared from chimaeric livers of these rats and transplanted into the spleen of DPPIV negative rats. Four weeks later, the expression of DPPIV in CK7 positive ductules in the spleen was examined by immunofluorescent double-staining. In the spleen of DPPIV negative rats transplanted with hepatocytes prepared from the chimaeric livers, DPPIV was found to be expressed in some CK7 positive biliary ductules where only a fraction of Cells expressed DPPIV, whereas in the spleen of DPPIV negative rats transplanted with hepatocytes from livers of DPPIV positive rats, DPPIV was expressed in all CK7 positive biliary ductules. The present study indicates that hepatocytes transplanted into the spleen could transdifferentiate into biliary Cells that aggregate to form Ductular structures.
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The origin of biliary Ductular Cells that appear in the spleen after transplantation of hepatocytes.
Cell transplantation, 2004Co-Authors: Kenji Fukuda, Naoko Yamada, Keiji Nakasho, Ayako Sugihara, Tohru Tsujimura, Atsuhito Okaya, Masafumi Sakagami, Nobuyuki TeradaAbstract:Transplantation of rat hepatocytes into the syngeneic rat spleen results in the appearance of cytokeration (CK)-19-positive biliary Cells that form ductules. The exact origin of CK-19-positive Cells is not known and the possibility that they are derived from biliary Cells or precursors of oval Cells in transplanted hepatocyte preparations has been raised. In the present study, we found that the number of CK-19-positive biliary Cells increased rapidly after transplantation of hepatocytes, reached the maximum at 4 weeks, and then gradually decreased. However, a Ki-67 labeling index of CK-19-positive biliary Cells was low and showed no significant changes throughout the experimental period. In addition, no or few CK-19-positive Cells appeared in the spleen after transplantation of nonparenchymal liver Cells enriched with biliary Cells. These results showed that biliary Cells were not the source of CK-19-positive Cells in the spleen. Impairment of precursors of oval Cells in the liver by administration of 4,4'-diaminodiphenylmethane 24 h before transplantation of hepatocytes did not prevent the appearance of CK-19-positive biliary Cells in the spleen. Moreover, transplantation of nonparenchymal Cells carrying an increased number of oval Cells by means of treatment with 2-acetylaminofluorene and partial hepatectomy resulted in no appearance of CK-19-positive biliary Cells in the spleen. These results ruled out oval Cells as the origin of CK-19-positive biliary Cells in the spleen. Because CK-19-positive biliary Cells appeared in the spleen only when hepatocyte fractions were transplanted, we suggest transdifferentiation of heptocytes may be the mechanism by which CK-19-positive biliary Cells are generated.
Yasuni Nakanuma - One of the best experts on this subject based on the ideXlab platform.
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IHC and PAS staining for serial sections of DDC-fed mice liver.
2017Co-Authors: Tomoki Yagai, Yasuni Nakanuma, Satoshi Matsui, Kenichi Harada, Fuyuki F. Inagaki, Eiko Saijou, Yasushi Miura, Atsushi Miyajima, Minoru TanakaAbstract:(A) Immunostaining of SAMD5 and CK19 for DDC-fed mice liver. SAMD5 is markedly expressed in several PBGs (solid arrows) and columnar mucus-producing cholangiocytes (open arrows) at the hepatic hilum, whereas SAMD5 is not detected in cuboidal Ductular Cells (arrow heads). (B) PAS staining for the serial section of panel (A). Mucin is stained violet, while deposition of Iron and bile plug is observed as red and black agglutination. Mucin is detected in hilar large bile duct and PBG, but not in cuboidal Ductular Cells (arrow heads). The lower panel is a magnified image of the upper panel. Bars = 100 μm.
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Cellular senescence in biliary pathology. Special emphasis on expression of a polycomb group protein EZH2 and a senescent marker p16INK4a in bile Ductular tumors and lesions.
Histology and histopathology, 2014Co-Authors: Motoko Sasaki, Yasuni NakanumaAbstract:A subgroup of intrahepatic cholangiocarcinoma and combined hepatocellular- cholangiocarcinoma contain a component of cholangiolocellular carcinoma, which is composed of small bile Ductular Cells. Ductular reaction, a reactive lesion at the portal tract interface comprising increased bile ductules, is frequently seen in chronic advanced liver diseases. Bile duct adenoma, a benign tumor/tumorous lesion is also composed of bile Ductular Cells. Differential diagnosis among these bile Ductular tumors/lesions is sometimes difficult. Given overexpression of a polycomb group protein EZH2 in intrahepatic cholangiocarcinoma and high expression of senescence-associated p16INK4a in Ductular reactions, we plan to apply immunostaining for EZH2 and p16INK4a for differential diagnosis of these bile Ductular tumors/lesions. The expression of EZH2 was seen in all cases of cholangiolocellular carcinomas, while it was not observed in bile duct adenomas or Ductular reactions. In contrast, the expression of p16INK4a was seen in most bile duct adenomas and all Ductular reactions, whereas it was barely seen in cholangiolocellular carcinomas. A borderline between cholangiolocellular carcinoma and the surrounding Ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16INK4a. In conclusion, immunostaining for EZH2 and p16INK4a may be useful for differential diagnosis for bile Ductular tumors/lesions.
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autophagy may precede cellular senescence of bile Ductular Cells in Ductular reaction in primary biliary cirrhosis
Digestive Diseases and Sciences, 2012Co-Authors: Motoko Sasaki, Masami Miyakoshi, Yasunori Sato, Yasuni NakanumaAbstract:Background and Aim Recent studies disclosed that autophagy facilitates the process of senescence. Given that cellular senescence is involved in the pathophysiology of Ductular reaction (DR) in primary biliary cirrhosis (PBC), we examined an involvement of autophagy in DRs in PBC and control livers.
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Autophagy May Precede Cellular Senescence of Bile Ductular Cells in Ductular Reaction in Primary Biliary Cirrhosis
Digestive diseases and sciences, 2011Co-Authors: Motoko Sasaki, Masami Miyakoshi, Yasunori Sato, Yasuni NakanumaAbstract:Recent studies disclosed that autophagy facilitates the process of senescence. Given that cellular senescence is involved in the pathophysiology of Ductular reaction (DR) in primary biliary cirrhosis (PBC), we examined an involvement of autophagy in DRs in PBC and control livers. We examined immunohistochemically the expression of microtubule-associated proteins light chain 3β (LC3) as autophagy marker, p62/sequestosome-1 (p62) as autophagy-related marker in bile Ductular Cells in livers taken from the patients with PBC (n = 42), and control livers (n = 100). The expression of senescent markers (p16(INK4a) and p21(WAF1/Cip1)) in bile Ductular Cells and their correlation with autophagy was also evaluated. The expression of LC3 was seen in coarse vesicles in the cytoplasm of bile Ductular Cells and significantly more frequently in PBC of both early and advanced stages when compared to control livers (p < 0.01). The expression of p62 was seen as intracytoplasmic aggregates and significantly more frequently in PBC when compared to control livers (p < 0.05). The expression of LC3 and p62 significantly correlated with each other (p < 0.01). The expression of LC3 and p62 significantly correlated with the expression of p16(INK4a), p21(WAF1/Cip1) (p < 0.05). Autophagy is frequently seen in bile Ductular Cells in DRs in PBC. Since cellular senescence of bile Ductular Cells is rather frequent in the advanced stage of PBC, autophagy may precede cellular senescence of bile Ductular Cells in DRs in PBC.
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Participation of bile Ductular Cells in the pathological progression of non-alcoholic fatty liver disease.
Journal of clinical pathology, 2011Co-Authors: Mayumi Chiba, Motoko Sasaki, Yasunori Sato, Hiroko Ikeda, Seiko Kitamura, Yasuni NakanumaAbstract:Aims Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathological conditions, ranging from simple steatosis to hepatic fibrosis with progression to cirrhosis. While activated hepatic stellate Cells (HSC) are known to be involved in intralobular, perisinuosidal fibrosis, the mechanisms of portal and bridging fibrosis remain speculative. This study investigated the roles of bile ductules in portal and septal fibrosis. Methods 48 liver biopsies were obtained from NAFLD patients. These cases were divided into four stages according to the Brunt classification. Results Bile ductules positive for CK19 were increased along with the progression of staging and fibrosis of NAFLD, and the increased bile ductules were associated with portal inflammation and fibrosis. The cellular senescence marker; p16INK4a and p21WAF1/Cip1-positive bile Ductular Cells were increased in stages 3 and 4. Such senescent bile ductules frequently express chemotactic protein, CCL2 (MCP-1), which may be responsible for chemoattraction of activated HSC around the bile ductules in portal and septal fibrosis and for portal inflammation. The migration of cultured mouse HSC was significantly facilitated in the presence of cultured senescent mouse biliary epithelial Cells (BEC), and this migration was mediated by CCL2 secreted from senescent cultured BEC. Small spindle-like Cells positive for CK7 alone in the hepatic parenchyma in the advanced stage seem to differentiate to periportal bile Ductular Cells positive for CK19 and CK7. Conclusions It seems possible that increased bile ductules expressing cellular senescence markers and chemokines are at least partly involved in the progressive portal and bridging fibrosis in NAFLD.
Nobuyuki Terada - One of the best experts on this subject based on the ideXlab platform.
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transdifferentiation into biliary Ductular Cells of hepatocytes transplanted into the spleen
Pathology, 2008Co-Authors: Hirofumi Watanabe, Masaki Hata, Nobuyuki Terada, Haruyasu Ueda, Naoko Yamada, Koji Yamanegi, Hideki Ohyama, Michiko Kakihana, Haruki Okamura, Keiji NakashoAbstract:Summary Aims Transplantation of rat hepatocytes into the syngeneic rat spleen results in the appearance of cytokeratin (CK)7 and CK19 positive biliary Cells that form ductules. We examined whether hepatocytes are the origin of these biliary Ductular Cells. Methods We transplanted rat dipeptidyl peptidase IV (DPPIV) positive hepatocytes into the liver of retrorsinetreated and partially hepatectomised DPPIV negative rats, which resulted in proliferation of DPPIV positive hepatocytes in the liver. Two months later, hepatocytes were prepared from chimaeric livers of these rats and transplanted into the spleen of DPPIV negative rats. Four weeks later, the expression of DPPIV in CK7 positive ductules in the spleen was examined by immunofluorescent double-staining. Results In the spleen of DPPIV negative rats transplanted with hepatocytes prepared from the chimaeric livers, DPPIV was found to be expressed in some CK7 positive biliary ductules where only a fraction of Cells expressed DPPIV, whereas in the spleen of DPPIV negative rats transplanted with hepatocytes from livers of DPPIV positive rats, DPPIV was expressed in all CK7 positive biliary ductules. Conclusion The present study indicates that hepatocytes transplanted into the spleen could transdifferentiate into biliary Cells that aggregate to form Ductular structures.
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Transdifferentiation into biliary Ductular Cells of hepatocytes transplanted into the spleen
Pathology, 2008Co-Authors: Hirofumi Watanabe, Masaki Hata, Nobuyuki Terada, Haruyasu Ueda, Naoko Yamada, Koji Yamanegi, Hideki Ohyama, Michiko Kakihana, Haruki Okamura, Keiji NakashoAbstract:Transplantation of rat hepatocytes into the syngeneic rat spleen results in the appearance of cytokeratin (CK)7 and CK19 positive biliary Cells that form ductules. We examined whether hepatocytes are the origin of these biliary Ductular Cells. We transplanted rat dipeptidyl peptidase IV (DPPIV) positive hepatocytes into the liver of retrorsine-treated and partially hepatectomised DPPIV negative rats, which resulted in proliferation of DPPIV positive hepatocytes in the liver. Two months later, hepatocytes were prepared from chimaeric livers of these rats and transplanted into the spleen of DPPIV negative rats. Four weeks later, the expression of DPPIV in CK7 positive ductules in the spleen was examined by immunofluorescent double-staining. In the spleen of DPPIV negative rats transplanted with hepatocytes prepared from the chimaeric livers, DPPIV was found to be expressed in some CK7 positive biliary ductules where only a fraction of Cells expressed DPPIV, whereas in the spleen of DPPIV negative rats transplanted with hepatocytes from livers of DPPIV positive rats, DPPIV was expressed in all CK7 positive biliary ductules. The present study indicates that hepatocytes transplanted into the spleen could transdifferentiate into biliary Cells that aggregate to form Ductular structures.
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The origin of biliary Ductular Cells that appear in the spleen after transplantation of hepatocytes.
Cell transplantation, 2004Co-Authors: Kenji Fukuda, Naoko Yamada, Keiji Nakasho, Ayako Sugihara, Tohru Tsujimura, Atsuhito Okaya, Masafumi Sakagami, Nobuyuki TeradaAbstract:Transplantation of rat hepatocytes into the syngeneic rat spleen results in the appearance of cytokeration (CK)-19-positive biliary Cells that form ductules. The exact origin of CK-19-positive Cells is not known and the possibility that they are derived from biliary Cells or precursors of oval Cells in transplanted hepatocyte preparations has been raised. In the present study, we found that the number of CK-19-positive biliary Cells increased rapidly after transplantation of hepatocytes, reached the maximum at 4 weeks, and then gradually decreased. However, a Ki-67 labeling index of CK-19-positive biliary Cells was low and showed no significant changes throughout the experimental period. In addition, no or few CK-19-positive Cells appeared in the spleen after transplantation of nonparenchymal liver Cells enriched with biliary Cells. These results showed that biliary Cells were not the source of CK-19-positive Cells in the spleen. Impairment of precursors of oval Cells in the liver by administration of 4,4'-diaminodiphenylmethane 24 h before transplantation of hepatocytes did not prevent the appearance of CK-19-positive biliary Cells in the spleen. Moreover, transplantation of nonparenchymal Cells carrying an increased number of oval Cells by means of treatment with 2-acetylaminofluorene and partial hepatectomy resulted in no appearance of CK-19-positive biliary Cells in the spleen. These results ruled out oval Cells as the origin of CK-19-positive biliary Cells in the spleen. Because CK-19-positive biliary Cells appeared in the spleen only when hepatocyte fractions were transplanted, we suggest transdifferentiation of heptocytes may be the mechanism by which CK-19-positive biliary Cells are generated.
Motoko Sasaki - One of the best experts on this subject based on the ideXlab platform.
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Cellular senescence in biliary pathology. Special emphasis on expression of a polycomb group protein EZH2 and a senescent marker p16INK4a in bile Ductular tumors and lesions.
Histology and histopathology, 2014Co-Authors: Motoko Sasaki, Yasuni NakanumaAbstract:A subgroup of intrahepatic cholangiocarcinoma and combined hepatocellular- cholangiocarcinoma contain a component of cholangiolocellular carcinoma, which is composed of small bile Ductular Cells. Ductular reaction, a reactive lesion at the portal tract interface comprising increased bile ductules, is frequently seen in chronic advanced liver diseases. Bile duct adenoma, a benign tumor/tumorous lesion is also composed of bile Ductular Cells. Differential diagnosis among these bile Ductular tumors/lesions is sometimes difficult. Given overexpression of a polycomb group protein EZH2 in intrahepatic cholangiocarcinoma and high expression of senescence-associated p16INK4a in Ductular reactions, we plan to apply immunostaining for EZH2 and p16INK4a for differential diagnosis of these bile Ductular tumors/lesions. The expression of EZH2 was seen in all cases of cholangiolocellular carcinomas, while it was not observed in bile duct adenomas or Ductular reactions. In contrast, the expression of p16INK4a was seen in most bile duct adenomas and all Ductular reactions, whereas it was barely seen in cholangiolocellular carcinomas. A borderline between cholangiolocellular carcinoma and the surrounding Ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16INK4a. In conclusion, immunostaining for EZH2 and p16INK4a may be useful for differential diagnosis for bile Ductular tumors/lesions.
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autophagy may precede cellular senescence of bile Ductular Cells in Ductular reaction in primary biliary cirrhosis
Digestive Diseases and Sciences, 2012Co-Authors: Motoko Sasaki, Masami Miyakoshi, Yasunori Sato, Yasuni NakanumaAbstract:Background and Aim Recent studies disclosed that autophagy facilitates the process of senescence. Given that cellular senescence is involved in the pathophysiology of Ductular reaction (DR) in primary biliary cirrhosis (PBC), we examined an involvement of autophagy in DRs in PBC and control livers.
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Autophagy May Precede Cellular Senescence of Bile Ductular Cells in Ductular Reaction in Primary Biliary Cirrhosis
Digestive diseases and sciences, 2011Co-Authors: Motoko Sasaki, Masami Miyakoshi, Yasunori Sato, Yasuni NakanumaAbstract:Recent studies disclosed that autophagy facilitates the process of senescence. Given that cellular senescence is involved in the pathophysiology of Ductular reaction (DR) in primary biliary cirrhosis (PBC), we examined an involvement of autophagy in DRs in PBC and control livers. We examined immunohistochemically the expression of microtubule-associated proteins light chain 3β (LC3) as autophagy marker, p62/sequestosome-1 (p62) as autophagy-related marker in bile Ductular Cells in livers taken from the patients with PBC (n = 42), and control livers (n = 100). The expression of senescent markers (p16(INK4a) and p21(WAF1/Cip1)) in bile Ductular Cells and their correlation with autophagy was also evaluated. The expression of LC3 was seen in coarse vesicles in the cytoplasm of bile Ductular Cells and significantly more frequently in PBC of both early and advanced stages when compared to control livers (p < 0.01). The expression of p62 was seen as intracytoplasmic aggregates and significantly more frequently in PBC when compared to control livers (p < 0.05). The expression of LC3 and p62 significantly correlated with each other (p < 0.01). The expression of LC3 and p62 significantly correlated with the expression of p16(INK4a), p21(WAF1/Cip1) (p < 0.05). Autophagy is frequently seen in bile Ductular Cells in DRs in PBC. Since cellular senescence of bile Ductular Cells is rather frequent in the advanced stage of PBC, autophagy may precede cellular senescence of bile Ductular Cells in DRs in PBC.
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Participation of bile Ductular Cells in the pathological progression of non-alcoholic fatty liver disease.
Journal of clinical pathology, 2011Co-Authors: Mayumi Chiba, Motoko Sasaki, Yasunori Sato, Hiroko Ikeda, Seiko Kitamura, Yasuni NakanumaAbstract:Aims Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathological conditions, ranging from simple steatosis to hepatic fibrosis with progression to cirrhosis. While activated hepatic stellate Cells (HSC) are known to be involved in intralobular, perisinuosidal fibrosis, the mechanisms of portal and bridging fibrosis remain speculative. This study investigated the roles of bile ductules in portal and septal fibrosis. Methods 48 liver biopsies were obtained from NAFLD patients. These cases were divided into four stages according to the Brunt classification. Results Bile ductules positive for CK19 were increased along with the progression of staging and fibrosis of NAFLD, and the increased bile ductules were associated with portal inflammation and fibrosis. The cellular senescence marker; p16INK4a and p21WAF1/Cip1-positive bile Ductular Cells were increased in stages 3 and 4. Such senescent bile ductules frequently express chemotactic protein, CCL2 (MCP-1), which may be responsible for chemoattraction of activated HSC around the bile ductules in portal and septal fibrosis and for portal inflammation. The migration of cultured mouse HSC was significantly facilitated in the presence of cultured senescent mouse biliary epithelial Cells (BEC), and this migration was mediated by CCL2 secreted from senescent cultured BEC. Small spindle-like Cells positive for CK7 alone in the hepatic parenchyma in the advanced stage seem to differentiate to periportal bile Ductular Cells positive for CK19 and CK7. Conclusions It seems possible that increased bile ductules expressing cellular senescence markers and chemokines are at least partly involved in the progressive portal and bridging fibrosis in NAFLD.
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Bile Ductular Cells Undergoing Cellular Senescence Increase in Chronic Liver Diseases Along With Fibrous Progression
American journal of clinical pathology, 2010Co-Authors: Motoko Sasaki, Masami Miyakoshi, Yasunori Sato, Hiroko Ikeda, Junpei Yamaguchi, Yasuni NakanumaAbstract:We investigated the pathologic significance of Ductular reactions in chronic liver diseases with respect to cellular senescence. The expression of senescence-associated markers (p16(INK4a) and p21(WAF1/Cip1)), cell proliferation, cell cycle markers (cyclin D and cyclin A), and neural cell adhesion molecule (NCAM) was examined immunohistochemically in primary biliary cirrhosis (PBC, n = 37), chronic viral hepatitis (n = 39), nonalcoholic steatohepatitis (n = 25), and control normal livers (n = 12). The expression of p16(INK4a) and p21(WAF1/Cip1) was frequently found in Ductular Cells in the advanced stage of chronic liver diseases, especially in PBC (P < .05). Double immunostaining disclosed that most senescent Cells expressed cyclin D (G(1)-phase marker). NCAM was frequently coexpressed in Ductular Cells showing senescence-associated markers. Some Ductular Cells in Ductular reactions in chronic liver diseases were at G(1) arrest and undergoing cellular senescence. Such senescent Cells may be involved in the progression of fibrosis of these diseases, particularly in PBC.
Naoko Yamada - One of the best experts on this subject based on the ideXlab platform.
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transdifferentiation into biliary Ductular Cells of hepatocytes transplanted into the spleen
Pathology, 2008Co-Authors: Hirofumi Watanabe, Masaki Hata, Nobuyuki Terada, Haruyasu Ueda, Naoko Yamada, Koji Yamanegi, Hideki Ohyama, Michiko Kakihana, Haruki Okamura, Keiji NakashoAbstract:Summary Aims Transplantation of rat hepatocytes into the syngeneic rat spleen results in the appearance of cytokeratin (CK)7 and CK19 positive biliary Cells that form ductules. We examined whether hepatocytes are the origin of these biliary Ductular Cells. Methods We transplanted rat dipeptidyl peptidase IV (DPPIV) positive hepatocytes into the liver of retrorsinetreated and partially hepatectomised DPPIV negative rats, which resulted in proliferation of DPPIV positive hepatocytes in the liver. Two months later, hepatocytes were prepared from chimaeric livers of these rats and transplanted into the spleen of DPPIV negative rats. Four weeks later, the expression of DPPIV in CK7 positive ductules in the spleen was examined by immunofluorescent double-staining. Results In the spleen of DPPIV negative rats transplanted with hepatocytes prepared from the chimaeric livers, DPPIV was found to be expressed in some CK7 positive biliary ductules where only a fraction of Cells expressed DPPIV, whereas in the spleen of DPPIV negative rats transplanted with hepatocytes from livers of DPPIV positive rats, DPPIV was expressed in all CK7 positive biliary ductules. Conclusion The present study indicates that hepatocytes transplanted into the spleen could transdifferentiate into biliary Cells that aggregate to form Ductular structures.
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Transdifferentiation into biliary Ductular Cells of hepatocytes transplanted into the spleen
Pathology, 2008Co-Authors: Hirofumi Watanabe, Masaki Hata, Nobuyuki Terada, Haruyasu Ueda, Naoko Yamada, Koji Yamanegi, Hideki Ohyama, Michiko Kakihana, Haruki Okamura, Keiji NakashoAbstract:Transplantation of rat hepatocytes into the syngeneic rat spleen results in the appearance of cytokeratin (CK)7 and CK19 positive biliary Cells that form ductules. We examined whether hepatocytes are the origin of these biliary Ductular Cells. We transplanted rat dipeptidyl peptidase IV (DPPIV) positive hepatocytes into the liver of retrorsine-treated and partially hepatectomised DPPIV negative rats, which resulted in proliferation of DPPIV positive hepatocytes in the liver. Two months later, hepatocytes were prepared from chimaeric livers of these rats and transplanted into the spleen of DPPIV negative rats. Four weeks later, the expression of DPPIV in CK7 positive ductules in the spleen was examined by immunofluorescent double-staining. In the spleen of DPPIV negative rats transplanted with hepatocytes prepared from the chimaeric livers, DPPIV was found to be expressed in some CK7 positive biliary ductules where only a fraction of Cells expressed DPPIV, whereas in the spleen of DPPIV negative rats transplanted with hepatocytes from livers of DPPIV positive rats, DPPIV was expressed in all CK7 positive biliary ductules. The present study indicates that hepatocytes transplanted into the spleen could transdifferentiate into biliary Cells that aggregate to form Ductular structures.
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The origin of biliary Ductular Cells that appear in the spleen after transplantation of hepatocytes.
Cell transplantation, 2004Co-Authors: Kenji Fukuda, Naoko Yamada, Keiji Nakasho, Ayako Sugihara, Tohru Tsujimura, Atsuhito Okaya, Masafumi Sakagami, Nobuyuki TeradaAbstract:Transplantation of rat hepatocytes into the syngeneic rat spleen results in the appearance of cytokeration (CK)-19-positive biliary Cells that form ductules. The exact origin of CK-19-positive Cells is not known and the possibility that they are derived from biliary Cells or precursors of oval Cells in transplanted hepatocyte preparations has been raised. In the present study, we found that the number of CK-19-positive biliary Cells increased rapidly after transplantation of hepatocytes, reached the maximum at 4 weeks, and then gradually decreased. However, a Ki-67 labeling index of CK-19-positive biliary Cells was low and showed no significant changes throughout the experimental period. In addition, no or few CK-19-positive Cells appeared in the spleen after transplantation of nonparenchymal liver Cells enriched with biliary Cells. These results showed that biliary Cells were not the source of CK-19-positive Cells in the spleen. Impairment of precursors of oval Cells in the liver by administration of 4,4'-diaminodiphenylmethane 24 h before transplantation of hepatocytes did not prevent the appearance of CK-19-positive biliary Cells in the spleen. Moreover, transplantation of nonparenchymal Cells carrying an increased number of oval Cells by means of treatment with 2-acetylaminofluorene and partial hepatectomy resulted in no appearance of CK-19-positive biliary Cells in the spleen. These results ruled out oval Cells as the origin of CK-19-positive biliary Cells in the spleen. Because CK-19-positive biliary Cells appeared in the spleen only when hepatocyte fractions were transplanted, we suggest transdifferentiation of heptocytes may be the mechanism by which CK-19-positive biliary Cells are generated.
