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Canadas RF, Costa JB, Mao Z, Gao C, Demirci U, Reis RL, Marques AP, Oliveira JM. 3DICE coding matrix multidirectional macro-architecture modulates cell organization, shape, and co-cultures endothelization network. Biomaterials 2021; 277:121112. [PMID: 34488122 DOI: 10.1016/j.biomaterials.2021.121112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/31/2021] [Accepted: 08/27/2021] [Indexed: 12/31/2022]
Abstract
Natural extracellular matrix governs cells providing biomechanical and biofunctional outstanding properties, despite being porous and mostly made of soft materials. Among organs, specific tissues present specialized macro-architectures. For instance, hepatic lobules present radial organization, while vascular sinusoids are branched from vertical veins, providing specific biofunctional features. Therefore, it is imperative to mimic such structures while modeling tissues. So far, there is limited capability of coupling oriented macro-structures with interconnected micro-channels in programmable long-range vertical and radial sequential orientations. Herein, a three-directional ice crystal elongation (3DICE) system is presented to code geometries in cryogels. Using 3DICE, guided ice crystals growth templates vertical and radial pores through bulky cryogels. Translucent isotropic and anisotropic architectures of radial or vertical pores are fabricated with tunable mechanical response. Furthermore, 3D combinations of vertical and radial pore orientations are coded at the centimeter scale. Cell morphological response to macro-architectures is demonstrated. The formation of endothelial segments, CYP450 activity, and osteopontin expression, as liver fibrosis biomarkers, present direct response and specific cellular organization within radial, linear, and random architectures. These results unlock the potential of ice-templating demonstrating the relevance of macro-architectures to model tissues, and broad possibilities for drug testing, tissue engineering, and regenerative medicine.
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Affiliation(s)
- Raphaël F Canadas
- 3B's Research Group, I3Bs, Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Zona Industrial da Gandra, AvePark, Barco GMR, 4805-017, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga, Guimarães, Portugal; Tech4MED™, UPTEC, ASPRELA I, Office-Lab 0.16, Business Campus, n.° 455/461, 4200-135 Porto, Portugal.
| | - João B Costa
- 3B's Research Group, I3Bs, Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Zona Industrial da Gandra, AvePark, Barco GMR, 4805-017, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Zhengwei Mao
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, China
| | - Changyou Gao
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, China
| | - Utkan Demirci
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford School of Medicine, Palo Alto, CA, 94304, USA; Electrical Engineering Department by Courtesy, Stanford University, Stanford, CA, 94305, USA
| | - Rui L Reis
- 3B's Research Group, I3Bs, Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Zona Industrial da Gandra, AvePark, Barco GMR, 4805-017, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Alexandra P Marques
- 3B's Research Group, I3Bs, Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Zona Industrial da Gandra, AvePark, Barco GMR, 4805-017, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Joaquim M Oliveira
- 3B's Research Group, I3Bs, Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Zona Industrial da Gandra, AvePark, Barco GMR, 4805-017, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga, Guimarães, Portugal.
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Tsomaia K, Patarashvili L, Karumidze N, Bebiashvili I, Azmaipharashvili E, Modebadze I, Dzidziguri D, Sareli M, Gusev S, Kordzaia D. Liver structural transformation after partial hepatectomy and repeated partial hepatectomy in rats: A renewed view on liver regeneration. World J Gastroenterol 2020; 26:3899-3916. [PMID: 32774065 PMCID: PMC7385567 DOI: 10.3748/wjg.v26.i27.3899] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/12/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The phenomenon of liver regeneration after partial hepatectomy (PH) is still a subject of considerable interest due to the increasing frequency of half liver transplantation on the one hand, and on the other hand, new surgical approaches which allow removal of massive space-occupying hepatic tumors, which earlier was considered as inoperable. Interestingly, the mechanisms of liver regeneration are extensively studied after PH but less attention is paid to the architectonics of the regenerated organ. Because of this, the question "How does the structure of regenerated liver differ from normal, regular liver?" has not been fully answered yet. Furthermore, almost without any attention is left the liver's structural transformation after repeated hepatectomy (of the re-regenereted liver). AIM To compare the architectonics of the lobules and circulatory bed of normal, re-generated and re-regenerated livers. METHODS The livers of 40 adult, male, albino Wistar rats were studied. 14 rats were subjected to PH - the 1st study group (SG1); 10 rats underwent repeated PH - the 2nd study group (SG2); 16 rats were subjected to sham operation - control group (CG); The livers were studied after 9 months from PH, and after 6 months from repeated PH. Cytological (Schiff reaction for the determination of DNA concen-tration), histological (H&E, Masson trichrome, CK8 Immunohistochemical marker, transparent slides after Indian Ink injection, ), morphometrical (hepatocytes areas, perimeters and ploidy) and Electron Microscopical (Scanning Electron Microscopy of corrosion casts) methods were used. RESULTS In the SG1 and SG2, the area of hepatocytes and their perimeter are increased compared to the CG (P < 0.05). However, the areas and perimeters of the hepatocytes of the SG1 and SG2 groups reveal a lesser difference. In regenerated (SG1) and re-regenerated (SG2) livers, the hepatocytes form the remodeled lobules, which size (300-1200 µm) exceeds the sizes of the lobules from CG (300-600 µm). The remodeled lobules (especially the "mega-lobules" with the sizes 1000-1200 µm) contain the transformed meshworks of the sinusoids, the part of which is dilated asymmetrically. This meshwork might have originated from the several portal venules (interlobular and/or inlet). The boundaries between the adjacent lobules (including mega-lobules) are widened and filled by connective tissue fibers, which gives the liver parenchyma a nodular look. In SG2 the unevenness of sinusoid diameters, as well as the boundaries between the lobules (including the mega-lobules) are more vividly expressed in comparison with SG1. The liver tissue of both SG1 and SG2 is featured by the slightly expressed ductular reaction. CONCLUSION Regenerated and re-regenerated livers in comparison with normal liver contain hypertrophied hepatocytes with increased ploidy which together with transformed sinusoidal and biliary meshworks form the remodeled lobulli.
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Affiliation(s)
- Keti Tsomaia
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Leila Patarashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Nino Karumidze
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Irakli Bebiashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Elza Azmaipharashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Irina Modebadze
- Faculty of Exact and Natural Sciences, Ivane Javakhishvili Tbilisi State University, Tbilisi 0179, Georgia
| | - Diana Dzidziguri
- Faculty of Exact and Natural Sciences, Ivane Javakhishvili Tbilisi State University, Tbilisi 0179, Georgia
| | - Marom Sareli
- Department of Surgical Oncology (Surgery C), Chaim Sheba Medical Center at HaShomer, Tel Aviv 52621, Israel
| | - Sergey Gusev
- Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Dimitri Kordzaia
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
- Clinical Anatomy and Operative Surgery, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
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Tsomaia K, Patarashvili L, Bebiashvili I, Azmaiparashvili E, Kakabadze M, Jalabadze N, Sareli M, Gusev S, Kordzaia D. New corrosion cast media and its ability for SEM and light microscope investigation. Microsc Res Tech 2020; 83:778-789. [PMID: 32129926 DOI: 10.1002/jemt.23468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 01/21/2020] [Accepted: 02/18/2020] [Indexed: 02/05/2023]
Abstract
SEM of corrosion casts (CC) provides the opportunities to study the vessels and ducts in the phyllogenetic and ontogenetic (age-related) settings, as well as the pathogenesis, compensation, and sanogenesis in different diseases and experimental models. Along with the refinement of SEM CC, the requirements toward casting media (CM) as nontoxicity, low viscosity, quick polymerization, resistance to corrosion solutions, availability, and so on, gradually has developed. We aimed to adapt the sets widely used in dental practice toward the modern requirements to the CC. The following ratio of the components of Protacryl-M and Aycryl-C sets were used for the preparation CM-0.25 g MAYCRYL Powder +0.08 g Benzoyl Peroxide +5.0 ml Protacryl-M liquid component +0.2 Redont Colour (dye concentrate). The obtained solidifying mass was injected in the blood vessels and biliary ducts of the adult Wistar white rats. The SEM of CC of different organs' vascular networks, as well as a biliary tract, reveals that offered CM excellently replicates the forms and branching features of studied tubular structures of all sizes and gives the adequate imprinting of their luminal surfaces. Besides, CM may provide the replication of perivascular spaces and give the casts having no analogous in the appropriate literature. The CM prepared by us perfectly reproduces all possibilities of famous rubbers widely used for the casting of different vascular-ductular structures. Besides, it presents the new implications, which should be implemented in the profound research of the connective-tissue skeleton of different organs.
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Affiliation(s)
- Keti Tsomaia
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Leila Patarashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Irakli Bebiashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Elza Azmaiparashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Manana Kakabadze
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Nikoloz Jalabadze
- Institute of Physical Materials Science and Materials Technologies, Georgian Technical University, Tbilisi, Georgia
| | - Marom Sareli
- Department of Surgical Oncology (Surgery C), Chaim Sheba Medical Center at HaShomer, Ramat Gan, Israel
| | - Sergey Gusev
- Federal Research & Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - Dimitri Kordzaia
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
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Szücs A, Paku S, Sebestyén E, Nagy P, Dezső K. Postnatal, ontogenic liver growth accomplished by biliary/oval cell proliferation and differentiation. PLoS One 2020; 15:e0233736. [PMID: 32470002 PMCID: PMC7259787 DOI: 10.1371/journal.pone.0233736] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 05/11/2020] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION The liver is well known for its enormous regenerative capacity. If the hepatocytes are compromised the reserve stem cells can regrow the lost tissue by means of oval cells differentiating into hepatocytes. We were curious whether this standby system was able to compensate for ontogenic liver growth arrested by 2-acetylaminofluorene (AAF) treatment or if it can be influenced by cholic acid, known to promote liver growth in several reactions. METHODS (i) Four weeks-old (60-70g) male F344 rats were kept on standard chow and treated with solvent only, (ii) others were kept on 0,2% cholic acid (CA) enriched diet, (iii) treated with AAF, or (iiii) given a combination of CA diet and AAF treatment (AAF/CA). The proliferative response of epithelial cells was characterized by pulse bromodeoxyuridine labelling. The relative gene expression levels of senescence-related factors and bile acid receptors were determined by quantitative real-time polymerase chain reaction analysis. RESULTS AAF administration efficiently inhibited the physiological proliferation of hepatocytes in young, male F344 rats after weaning. The activation of stem cells was indicated by the increased proliferation of periportal biliary/oval cells (B/OC). If the rats were fed additionally by cholic acid enriched diet, typical oval cell reaction emerged, subsequently the oval cells differentiated into hepatocytes restituting liver growth. This reaction was mediated by increased production of HGF, IL-6 and SCF by the damaged liver. Moreover, upregulation of FXR expression on B/OC made them competent for bile acids. Our results indicate that endogenous, autocrine mechanisms involved in liver ontogeny are also able to activate the backup regenerative machinery of stem cells.
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Affiliation(s)
- Armanda Szücs
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Sándor Paku
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Endre Sebestyén
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Péter Nagy
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Katalin Dezső
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
- * E-mail:
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Adams JM, Huppert KA, Castro EC, Lopez MF, Niknejad N, Subramanian S, Zarrin-Khameh N, Finegold MJ, Huppert SS, Jafar-Nejad H. Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome. Hepatology 2020; 71:1331-1349. [PMID: 31469182 PMCID: PMC7048647 DOI: 10.1002/hep.30912] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 08/19/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIMS Alagille syndrome (ALGS) is a multisystem developmental disorder characterized by bile duct (BD) paucity, caused primarily by haploinsufficiency of the Notch ligand jagged1. The course of the liver disease is highly variable in ALGS. However, the genetic basis for ALGS phenotypic variability is unknown. Previous studies have reported decreased expression of the transcription factor SOX9 (sex determining region Y-box 9) in late embryonic and neonatal livers of Jag1-deficient mice. Here, we investigated the effects of altering the Sox9 gene dosage on the severity of liver disease in an ALGS mouse model. APPROACH AND RESULTS Conditional removal of one copy of Sox9 in Jag1+/- livers impairs the biliary commitment of cholangiocytes and enhances the inflammatory reaction and liver fibrosis. Loss of both copies of Sox9 in Jag1+/- livers further worsens the phenotypes and results in partial lethality. Ink injection experiments reveal impaired biliary tree formation in the periphery of P30 Jag1+/- livers, which is improved by 5 months of age. Sox9 heterozygosity worsens the P30 biliary tree phenotype and impairs the partial recovery in 5-month-old animals. Notably, Sox9 overexpression improves BD paucity and liver phenotypes in Jag1+/- mice without ectopic hepatocyte-to-cholangiocyte transdifferentiation or long-term liver abnormalities. Notch2 expression in the liver is increased following Sox9 overexpression, and SOX9 binds the Notch2 regulatory region in the liver. Histological analysis shows a correlation between the level and pattern of SOX9 expression in the liver and outcome of the liver disease in patients with ALGS. CONCLUSIONS Our results establish Sox9 as a dosage-sensitive modifier of Jag1+/- liver phenotypes with a permissive role in biliary development. Our data further suggest that liver-specific increase in SOX9 levels is a potential therapeutic approach for BD paucity in ALGS.
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Affiliation(s)
- Joshua M. Adams
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX
- Medical Scientist Training Program, Baylor College of Medicine, Houston, TX
| | - Kari A. Huppert
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Eumenia C. Castro
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX
- Department of Pathology, Texas Children’s Hospital, Houston, TX
| | - Mario F. Lopez
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Nima Niknejad
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Sanjay Subramanian
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Neda Zarrin-Khameh
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX
| | - Milton J. Finegold
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX
| | - Stacey S. Huppert
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Hamed Jafar-Nejad
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
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Dezső K, Nagy P, Paku S. Human liver regeneration following massive hepatic necrosis: Two distinct patterns. J Gastroenterol Hepatol 2020; 35:124-134. [PMID: 31090096 DOI: 10.1111/jgh.14721] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 05/04/2019] [Accepted: 05/07/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIM Massive hepatic necrosis is a rare but often fatal complication of various liver injuries. Nevertheless, some patients can survive by spontaneous hepatic regeneration. It is known that surviving hepatocytes and/or progenitor cells can participate in this process but the mechanism of hepatic recovery is vague. METHODS We examined 13 explanted human livers removed for acute liver failure. Combined immunohistochemistry, digital image analysis, and three-dimensional reconstruction of serial sections were applied. RESULTS Two patterns of regeneration could be distinguished. In livers with centrilobular necrosis, the surviving injured periportal hepatocytes started to proliferate and arrange into acinar structures and expressed α-fetoprotein. If the injury wiped out almost all hepatocytes, large areas of parenchymal loss were invaded by an intense ductular reaction. The cells at the distal pole of the ductules differentiated into hepatocytes and formed foci organized by the branches of the portal vein. The expanding foci often containing complete portal triads were arranged around surviving central veins. Their fusion eventually could be an attempt to re-establish the hepatic lobules. CONCLUSIONS Regeneration of human livers following massive hepatic necrosis can occur in two ways-either through proliferation of α-fetoprotein-positive acinary-arranged hepatocytes or through ductular progenitor cells, with the latter being less efficient. Further investigation of these regenerative pathways may help identify biomarkers for likelihood of complete regeneration and hence have therapeutic implications.
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Affiliation(s)
- Katalin Dezső
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Péter Nagy
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Sándor Paku
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
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Human liver regeneration in advanced cirrhosis is organized by the portal tree. J Hepatol 2017; 66:778-786. [PMID: 27913222 DOI: 10.1016/j.jhep.2016.11.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 11/08/2016] [Accepted: 11/13/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS In advanced cirrhosis new hepatocytic nodules are generated by budding of ductules in areas of parenchymal extinction. However, the vascular alterations in the areas of parenchymal extinction, the blood supply and the structure of the new hepatocytic nodules have not been analyzed in detail. METHODS Explanted human cirrhotic livers of three different etiologies and two experimental rat models of cirrhosis were thoroughly examined. 3D reconstruction of the immunohistochemically stained serial sections and casting of human and experimental cirrhotic livers have been used to reveal the structural organization of the regenerative buds. RESULTS In areas of parenchymal extinction the skeleton of the liver, the portal tree is preserved. The developing regenerative nodules are positioned along the portal tree and are directly supplied by terminal portal venules. The expanding nodules grow along the trunks of the portal vein. Casting of human and experimental cirrhotic livers by colored resin confirms that nodules are supplied by portal blood. The two other members of the portal triads become separated from the portal veins. CONCLUSIONS As the structure of the hepatocyte nodules (centrally located portal vein branches, bile ducts at the periphery, hepatic veins and arteries in the connective tissue) impedes the restoration of normal liver structure, the basic architecture of hepatic tissue suffers permanent damage. We suggest that "budding" may initiate the second, irreversible stage of cirrhosis. LAY SUMMARY Cirrhosis is the final common outcome of long lasting hepatic injury defined as the destruction of the normal liver architecture by scar tissue. In the late phase of cirrhosis stem cells-derived hepatocyte nodules appear along the branches of the portal vein suggesting an important role of this specially composed blood vessels (containing digestive end-products from the stomach and intestines) in liver regeneration. Our results contribute to a better understanding of this serious liver disease.
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Marongiu F, Marongiu M, Contini A, Serra M, Cadoni E, Murgia R, Laconi E. Hyperplasia vs hypertrophy in tissue regeneration after extensive liver resection. World J Gastroenterol 2017; 23:1764-1770. [PMID: 28348481 PMCID: PMC5352916 DOI: 10.3748/wjg.v23.i10.1764] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 12/27/2016] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To address to what extent hypertrophy and hyperplasia contribute to liver mass restoration after major tissue loss.
METHODS The ability of the liver to regenerate is remarkable on both clinical and biological grounds. Basic mechanisms underlying this process have been intensively investigated. However, it is still debated to what extent hypertrophy and hyperplasia contribute to liver mass restoration after major tissue loss. We addressed this issue using a genetically tagged system. We were able to follow the fate of single transplanted hepatocytes during the regenerative response elicited by 2/3 partial surgical hepatectomy (PH) in rats. Clusters of transplanted cells were 3D reconstructed and their size distribution was evaluated over time after PH.
RESULTS Liver size and liver DNA content were largely recovered 10 d post-PH, as expected (e.g., total DNA/liver/100 g b.w. was 6.37 ± 0.21 before PH and returned to 6.10 ± 0.36 10 d after PH). Data indicated that about 2/3 of the original residual hepatocytes entered S-phase in response to PH. Analysis of cluster size distribution at 24, 48, 96 h and 10 d after PH revealed that about half of the remnant hepatocytes completed at least 2 cell cycles. Average size of hepatocytes increased at 24 h (248.50 μm2 ± 7.82 μm2, P = 0.0015), but returned to control values throughout the regenerative process (up to 10 d post-PH, 197.9 μm2 ± 6.44 μm2, P = 0.11). A sizeable fraction of the remnant hepatocyte population does not participate actively in tissue mass restoration.
CONCLUSION Hyperplasia stands as the major mechanism contributing to liver mass restoration after PH, with hypertrophy playing a transient role in the process.
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Transaminase abnormalities and adaptations of the liver lobule manifest at specific cut-offs of steatosis. Sci Rep 2017; 7:40977. [PMID: 28106158 PMCID: PMC5247698 DOI: 10.1038/srep40977] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 12/13/2016] [Indexed: 01/18/2023] Open
Abstract
There is little documented evidence suggesting that liver fat is responsible for liver injury in the absence of other disease processes. We investigated the relationships between liver fat, aminotransferases and hepatic architecture in liver biopsies with simple steatosis. We identified 136 biopsies with simple steatosis from the Royal Free Hospital Archives with both clinical data and sufficient material. Digital image analysis was employed to measure fat proportionate area (mFPA). Hepatocyte area (HA) and lobule radius (LR) were also measured. There were significant increases in ALT (p < 0.001) and AST (p = 0.013) with increased fat content and evidence to suggest both 5% and 20% mFPA as a cut-off for raised ALT. In liver with increased fat content there were significant increases in HA (p < 0.001). LR also increased as mFPA increased to 10% (p < 0.001), at which point the lobule ceased to expand further and was counterbalanced with a decrease in the number of hepatocytes per lobule (p = 0.029). Consequently there are mechanisms of adaption in the liver architecture to accommodate the accumulation of fat and these are accompanied by significant increases in transaminases. These results support the generally accepted cut-off of 5% fat for steatosis and indicate 20% as a threshold of more severe liver injury.
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Ma D, Yu ZY. Current status of research on liver regeneration. Shijie Huaren Xiaohua Zazhi 2016; 24:4193-4199. [DOI: 10.11569/wcjd.v24.i30.4193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The liver has a strong regenerative potential, and liver regeneration shows different ways according to the degree of liver injury. The current research on liver regeneration has achieved some promising results, and the cellular and molecular mechanism of liver regeneration has been deeply studied. Recently, the role of biomechanical factors in liver regeneration is gradually attracting attention. In addition to the proliferation of liver cells, liver regeneration also involves the proliferation and differentiation of hepatic stem cells. However, the exact mechanism of liver regeneration is not fully clear. This review will summarize the relevant studies on liver regeneration to discuss the current research status of liver regeneration, with regard to the liver regeneration model, cellular and molecular mechanism of liver regeneration, the effects of mechanical factors on regeneration, and the role of stem cells in liver regeneration. A better understanding of liver regeneration will provide a new avenue for the clinical diagnosis and treatment of liver related diseases.
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Long live the liver: immunohistochemical and stereological study of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells of male and female rats throughout ageing. Cell Tissue Res 2016; 366:639-649. [DOI: 10.1007/s00441-016-2490-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 08/03/2016] [Indexed: 01/23/2023]
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Rathi S, Dhiman RK. Hepatobiliary Quiz Answers-19 (2016). J Clin Exp Hepatol 2016; 6:257-260. [PMID: 27746626 PMCID: PMC5052399 DOI: 10.1016/j.jceh.2016.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
| | - Radha K. Dhiman
- Address for correspondence: Radha K. Dhiman, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.Department of Hepatology, Postgraduate Institute of Medical Education and ResearchChandigarh160012India
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13
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Fülöp A, Budai A, Czigány Z, Lotz G, Dezső K, Paku S, Harsányi L, Szijártó A. Alterations in hepatic lobar function in regenerating rat liver. J Surg Res 2015; 197:307-17. [PMID: 25963167 DOI: 10.1016/j.jss.2015.04.033] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 03/16/2015] [Accepted: 04/09/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Ligation of a branch of the portal vein redirects portal blood to nonligated lobes resulting in lobar hypertrophy. Although the effect of portal vein ligation on liver volume is well documented, the parallel alterations in liver function are still the subject of controversy. Our aim was to assess the time-dependent reactions of regional hepatic function to portal vein ligation by selective biliary drainage. METHODS Male Wistar rats (n = 44) underwent 80% portal vein ligation. Before the operation as well as 1, 2, 3, 5, and 7 d after circulation, morphology and function (laboratory blood test; hepatic bile flow; plasma disappearance rate of indocyanine green; and biliary indocyanine green excretion) of the liver were examined. RESULTS Although portal vein ligation affected liver circulation and morphology to a great extent, serum albumin levels, bilirubin levels, and total hepatic bile flow did not change significantly after the operation. Nevertheless, plasma disappearance rate and biliary indocyanine green excretion indicated a temporary impairment of total liver function with the lowest value on the second day and normalization by the fifth day. Bile production and biliary indocyanine green excretion of ligated lobes decreased rapidly after the operation and remained persistently suppressed, whereas the secretory function of nonligated lobes--after a temporary decline--showed a greater increase than the weight of the lobes. CONCLUSIONS Portal vein ligation induced temporary impairment of total liver function, followed by rapid recovery mainly by reason of increase in the function of nonligated lobes. Functional increase in nonligated lobes was more pronounced than suggested by the degree of volume gain.
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Affiliation(s)
- András Fülöp
- 1st Department of Surgery, Semmelweis University, Budapest, Hungary
| | - András Budai
- 1st Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Zoltán Czigány
- 1st Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Gábor Lotz
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Katalin Dezső
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Sándor Paku
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; Tumor Progression Research Group, Joint Research Organization of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
| | - László Harsányi
- 1st Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Attila Szijártó
- 1st Department of Surgery, Semmelweis University, Budapest, Hungary.
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14
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Kandilis AN, Koskinas J, Vlachos I, Skaltsas S, Karandrea D, Karakitsos P, Pantopoulou A, Palaiologou M, Nikiteas N, Tiniakos DG, Perrea DN. Liver regeneration: immunohistochemical study of intrinsic hepatic innervation after partial hepatectomy in rats. BMC Gastroenterol 2014; 14:202. [PMID: 25421900 PMCID: PMC4247746 DOI: 10.1186/s12876-014-0202-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 11/11/2014] [Indexed: 01/28/2023] Open
Abstract
Background We examined the intrinsic hepatic innervation after partial hepatectomy (PH) in rats and the presence and pattern of neural sprouting in regenerating liver. Methods Male Wistar rats (age 9–13 weeks-w, weight 204-356 g), were submitted to two-thirds PH. Rats were sacrificed at postoperative days (d) 1, 3, 5, 7, at 2 and 4 w, and at 3 and 6 months (m) (6–7 animals/group, control group n = 4). Immunohistochemistry for the pan-neural marker protein gene product 9.5 (PGP9.5) and growth-associated protein 43 (GAP-43), a marker of regenerating nerve axons, was performed on tissue sections from the R1 lobe of the regenerating liver. Portal tracts (PTs) with immunoreactive fibers were counted in each section and computer-assisted morphometric analysis (Image Pro Plus) was used to measure nerve fiber density (number of immuno-positive nerve fibers/mm2 (40x)). Results Immunoreactivity for PGP9.5 was positive in all groups. The number of PGP9.5 (+) nerve fibers decreased from 0.32 +/− 0.12 (control group) to 0.18 +/− 0.09 (1d post-PH group), and gradually increased reaching pre-PH levels at 6 m (0.3 +/− 0.01). In contrast, immunoreactivity for GAP-43 was observed at 5d post-PH, and GAP-43 (+) PTs percentage increased thereafter with a peak at 3 m post-PH. GAP-43 (+) nerve fiber density increased gradually from 5d (0.05 +/− 0.06) with a peak at 3 m post-PH (0.21 +/− 0.027). At 6 m post-PH, immunoreactivity for GAP-43 was not detectable. Conclusions Following PH in rats: 1) nerve fiber density in portal tracts decreases temporarily, and 2) neural sprouting in the regenerating liver lobes starts at 5d, reaches peak levels at 3 m and disappears at 6 m post-PH, indicating that the increase in hepatic mass after PH provides an adequate stimulus for the sprouting process.
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15
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Abstract
Liver regeneration after partial hepatectomy is the only example of a regenerative process in mammals in which the organ/body weight ratio returns to 100% of the original when the process is complete. The adjustment of liver weight to the needs of the body suggests a complicated set of control points, a 'hepatostat'. There has been much progress in elucidation of mechanisms involved in initiation of liver regeneration. More recent studies have focused on termination pathways, because these may be the underlying controls of the hepatostat and their elimination may be relevant to hepatic neoplasia. When the standard regenerative process is thwarted due to failure of either hepatocytes or biliary epithelial cells to proliferate, each of the two epithelial compartments can function as a source of facultative stem cells for the other.
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Affiliation(s)
- George K Michalopoulos
- Department of Pathology, University of Pittsburgh School of Medicine, Bioscience Tower South, Pittsburgh, PA 15261, USA
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16
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How does a single cell know when the liver has reached its correct size? PLoS One 2014; 9:e93207. [PMID: 24690888 PMCID: PMC3972176 DOI: 10.1371/journal.pone.0093207] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Accepted: 03/02/2014] [Indexed: 01/19/2023] Open
Abstract
The liver is a multi-functional organ that regulates major physiological processes and that possesses a remarkable regeneration capacity. After loss of functional liver mass the liver grows back to its original, individual size through hepatocyte proliferation and apoptosis. How does a single hepatocyte 'know' when the organ has grown to its final size? This work considers the initial growth phase of liver regeneration after partial hepatectomy in which the mass is restored. There are strong and valid arguments that the trigger of proliferation after partial hepatectomy is mediated through the portal blood flow. It remains unclear, if either or both the concentration of metabolites in the blood or the shear stress are crucial to hepatocyte proliferation and liver size control. A cell-based mathematical model is developed that helps discriminate the effects of these two potential triggers. Analysis of the mathematical model shows that a metabolic load and a hemodynamical hypothesis imply different feedback mechanisms at the cellular scale. The predictions of the developed mathematical model are compared to experimental data in rats. The assumption that hepatocytes are able to buffer the metabolic load leads to a robustness against short-term fluctuations of the trigger which can not be achieved with a purely hemodynamical trigger.
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17
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Itoh T, Miyajima A. Liver regeneration by stem/progenitor cells. Hepatology 2014; 59:1617-26. [PMID: 24115180 DOI: 10.1002/hep.26753] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 09/11/2013] [Indexed: 12/12/2022]
Abstract
UNLABELLED The liver is renowned for its strong, robust regenerative capacity, employing different modes of regeneration according to type and extent of injury. The process of compensatory hypertrophy of the liver upon partial hepatectomy has been standing as a classical model for studying organ regeneration in mammals and a subject of exhaustive analyses. Meanwhile, in view of the physiological relevance for many of the human liver pathologies induced upon toxic insults or hepatitis, other injury models have recently drawn increasing attention. In those damaged livers where hepatocyte proliferation is compromised, adult liver stem/progenitor cells (LPCs) are activated and differentiate to hepatocytes and cholangiocytes, leading to functional recovery of the organ. Here, we summarize and discuss recent findings on the mechanisms underlying the regeneration process of the liver. Whereas the primary focus of this article is on those related to LPC-mediated regeneration, we also introduce topics on compensatory hypertrophy, where application of new technologies and molecular genetics approaches in mice has gained a paradigm shift. Identification of various markers for LPC populations has expedited their characterization and enabled us to examine their differentiation potential in vivo using genetic lineage-tracing approaches. Comprehensive studies regarding intercellular signaling pathways and their modes of action have succeeded in elucidating novel frameworks for the LPC-niche interaction functioning in the regenerating liver. CONCLUSION Advancing our understanding of the cellular and molecular mechanisms for liver regeneration should provide a basis for developing therapeutic strategies to treat patients with liver disease.
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Affiliation(s)
- Tohru Itoh
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
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18
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Pinna F, Sahle S, Beuke K, Bissinger M, Tuncay S, D'Alessandro LA, Gauges R, Raue A, Timmer J, Klingmüller U, Schirmacher P, Kummer U, Breuhahn K. A Systems Biology Study on NFκB Signaling in Primary Mouse Hepatocytes. Front Physiol 2012; 3:466. [PMID: 23293603 PMCID: PMC3533138 DOI: 10.3389/fphys.2012.00466] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2012] [Accepted: 11/26/2012] [Indexed: 12/14/2022] Open
Abstract
The cytokine tumor necrosis factor-alpha (TNFα) is one of the key factors during the priming phase of liver regeneration as well as in hepatocarcinogenesis. TNFα activates the nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) signaling pathway and contributes to the conversion of quiescent hepatocytes to activated hepatocytes that are able to proliferate in response to growth factor stimulation. Different mathematical models have been previously established for TNFα/NFκB signaling in the context of tumor cells. Combining these mathematical models with time-resolved measurements of expression and phosphorylation of TNFα/NFκB pathway constituents in primary mouse hepatocytes revealed that an additional phosphorylation step of the NFκB isoform p65 has to be considered in the mathematical model in order to sufficiently describe the dynamics of pathway activation in the primary cells. Also, we addressed the role of basal protein turnover by experimentally measuring the degradation rate of pivotal players in the absence of TNFα and including this information in the model. To elucidate the impact of variations in the protein degradation rates on TNFα/NFκB signaling on the overall dynamic behavior we used global sensitivity analysis that accounts for parameter uncertainties and showed that degradation and translation of p65 had a major impact on the amplitude and the integral of p65 phosphorylation. Finally, our mathematical model of TNFα/NFκB signaling was able to predict the time-course of the complex formation of p65 and of the inhibitor of NFκB (IκB) in primary mouse hepatocytes, which was experimentally verified. Hence, we here present a mathematical model for TNFα/NFκB signaling in primary mouse hepatocytes that provides an important basis to quantitatively disentangle the complex interplay of multiple factors in liver regeneration and tumorigenesis.
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Affiliation(s)
- Federico Pinna
- Institute of Pathology, University Hospital of Heidelberg Heidelberg, Germany
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Dezső K, Papp V, Bugyik E, Hegyesi H, Sáfrány G, Bödör C, Nagy P, Paku S. Structural analysis of oval-cell-mediated liver regeneration in rats. Hepatology 2012; 56:1457-67. [PMID: 22419534 DOI: 10.1002/hep.25713] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Accepted: 03/04/2012] [Indexed: 12/31/2022]
Abstract
UNLABELLED We have analyzed the architectural aspects of progenitor-cell-driven regenerative growth in rat liver by applying the 2-acetaminofluorene/partial hepatectomy experimental model. The regeneration is initiated by the proliferation of so-called oval cells. The oval cells at the proximal tips of the ductules have a more differentiated phenotype and higher proliferative rate. This preferential growth results in the formation of a seemingly random collection of small hepatocytes, called foci. These foci have no clonal origin, but possess a highly organized structure, which shows similarities to normal hepatic parenchyma. Therefore, they can easily remodel into the lobular structure. Eventually, the regenerated liver is constructed by enlarged hepatic lobules; no new lobules are formed during this process. The foci of the Solt-Farber experimental hepatocarcinogenesis model have identical morphological features; accordingly, they also represent only regenerative, not neoplastic, growth. CONCLUSION Progenitor-cell-driven liver regeneration is a well-designed, highly organized tissue reaction, and better comprehension of the architectural events may help us to recognize this process and understand its role in physiological and pathological reactions.
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Affiliation(s)
- Katalin Dezső
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
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Holzhütter HG, Drasdo D, Preusser T, Lippert J, Henney AM. The virtual liver: a multidisciplinary, multilevel challenge for systems biology. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2012; 4:221-35. [PMID: 22246674 DOI: 10.1002/wsbm.1158] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The liver is the central metabolic organ in human physiology, with functions that are fundamentally important to the detoxification of xenobiotics (drugs), the maintenance of homeostasis of numerous blood metabolites, and the production of mediators of the acute phase response. Liver toxicity, whether actual or implied is the reason for the failure of a significant proportion of many promising novel medicines that consequently never reach the market, and diseases such as atherosclerosis, diabetes, and fatty liver diseases, that are a major burden on current health resources, are directly linked to functional and structural disorders of the liver. This article presents the concepts and approaches underpinning one of the most exciting and ambitious modeling projects in the field of systems biology and systems medicine. This major multidisciplinary research program is aimed at developing a whole-organ model of the human liver, representing its central physiological functions under normal and pathological conditions The model will be composed of a larger battery of interconnected submodels representing liver anatomy and physiology, integrating processes across hierarchical levels in space, time, and structural organization. In this article, we outline the general architecture of the liver model and present first step taken to reach this ambitious goal.
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21
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Desmet VJ. Ductal plates in hepatic ductular reactions. Hypothesis and implications. II. Ontogenic liver growth in childhood. Virchows Arch 2011; 458:261-70. [PMID: 21298286 DOI: 10.1007/s00428-011-1049-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2010] [Revised: 01/18/2011] [Accepted: 01/18/2011] [Indexed: 01/09/2023]
Abstract
This article discusses the processes of bile duct growth and new lobule formation in the liver during childhood in the light of the ductal plate (DP) hypothesis. Unlike in other organs in which tubular elongation and branching ends with the creation of the organ-specific terminal differentiation products, in the liver a steadily enlarging parenchymal mass needs to establish continuity of its canalicular network with the existing bile duct system. The hypothesis suggests that this occurs by DP formation, like in the embryonic liver, and further assumes that pathological ductular reactions (DRs) induced by cholestasis or hypoxia are amplified equivalents of similar mechanisms operating at low level during liver growth. The concept is confronted with data on porcine liver growth, since swine and non-swine liver growth is thought to be comparable. Relative bile acid load may be the driving force for establishment of new canaliculo-ductular connections, supported in zones of relative hypoxia by hypoxia-inducible factor 1 alpha secreted by hepatocytes. The latter mechanism is at the base for induction of appropriate vascular changes in selected sinusoids, resulting in the development of portal inlet venules and additional draining central veins. The process gives rise to the formation of new single lobules by formation of new portal tracts or to the transformation of single lobules in compound lobules by development of new vascular septa. The concept of postnatal DP formation is important in the elucidation of several unexplained findings in adult liver diseases.
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Affiliation(s)
- Valeer J Desmet
- Department of Pathology, University Hospital K.U.Leuven, Rafael, Leuven, Belgium.
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22
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Dezso K, Paku S, Papp V, Turányi E, Nagy P. Architectural and immunohistochemical characterization of biliary ductules in normal human liver. Stem Cells Dev 2010; 18:1417-22. [PMID: 19552603 DOI: 10.1089/scd.2009.0110] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The canals of Hering or biliary ductules have been described to connect the bile canaliculi with the interlobular bile ducts, and thus forming the distal part of the biliary tree. Studies in the last two decades suggested that the cells constructing these ductules could behave as hepatic progenitor cells. The canals of Hering are confined to the periportal space in the rat, while they have been reported to spread beyond the limiting plate in human liver. The distribution of the distal biliary ductules in normal human hepatic tissue has been investigated in our recent experiments. We could demonstrate the presence of interlobular connective tissue septa in a rudimentary form in healthy livers. The canals of Hering run in these septa in line with the terminal branches of the portal vein and hepatic arteries. This arrangement develops in the postnatal period but regresses after early childhood. The canals of Hering can be identified by the unique epithelial membrane antigen (EMA)-/CD56+/CD133+ immunophenotype. The canals of Hering leave the periportal space and spread into the liver parenchyma along rudimentary interlobular septa outlining the hepatic lobules. Our observations refine the original architectural description of the intraparenchymal portion of the canals of Hering in the human liver. The distinct immunophenotype supports their unique biological function.
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Affiliation(s)
- Katalin Dezso
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest 1085, Hungary
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