scholarly journals Cholangiocarcinomas: New Insights from the Discovery of Stem Cell Niches in Peribiliary Glands of the Biliary Tree

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Vincenzo Cardinale ◽  
Maria Consiglia Bragazzi ◽  
Guido Carpino ◽  
Alessia Torrice ◽  
Yunfang Wang ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Adult Life ◽  
Biliary Tree ◽  
Ductal Adenocarcinoma ◽  
Fetal Life ◽  
Extrahepatic Bile Ducts ◽  
Glandular Structures ◽  
Peribiliary Glands ◽  
Endodermal Origin

Peribiliary glands (PBGs) are located in the large intrahepatic and extrahepatic bile ducts. Although they were described many years ago, their functions have been elucidated only in the last couple of years when our group demonstrated that PBGs are niches of multipotent stem/progenitor cells of endodermal origin. These cells express genes of multipotency and can be rapidly differentiated in vitro into hepatocytes, cholangiocytes, and endocrine pancreatic cells. PBGs share common features, in terms of stem/progenitor cell niches, with pancreatic duct glands and colon crypts, glandular structures representing in the adult life the endodermal remnants of fetal life. PBG stem/progenitor cells participate in the renewal of surface biliary epithelium and are active players in chronic pathologies of the biliary tree as well as in cholangiocarcinomas (CCA). Specifically, a large amount of recent evidence indicates that the pure mucin-CCA originates from PBGs; this could explain the similarities with pancreatic ductal adenocarcinoma and colorectal cancer, which also originate from transformed gland cells. In this paper, we summarized our recent findings concerning structure and functions of PBGs with the implications for liver pathophysiology and, specifically, for cancers of the biliary tree.

scholarly journals Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Guido Carpino ◽  
Anastasia Renzi ◽  
Antonio Franchitto ◽  
Vincenzo Cardinale ◽  
Paolo Onori ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Bile Ducts ◽  
Progenitor Cell ◽  
Stellate Cells ◽  
Biliary Tree ◽  
Central Vein ◽  
Cell Fates ◽  
Pancreatic Cell ◽  
Intrahepatic Bile Ducts ◽  
Peribiliary Glands

Niches containing stem/progenitor cells are present in different anatomical locations along the human biliary tree and within liver acini. The most primitive stem/progenitors, biliary tree stem/progenitor cells (BTSCs), reside within peribiliary glands located throughout large extrahepatic and intrahepatic bile ducts. BTSCs are multipotent and can differentiate towards hepatic and pancreatic cell fates. These niches’ matrix chemistry and other characteristics are undefined. Canals of Hering (bile ductules) are found periportally and contain hepatic stem/progenitor cells (HpSCs), participating in the renewal of small intrahepatic bile ducts and being precursors to hepatocytes and cholangiocytes. The niches also contain precursors to hepatic stellate cells and endothelia, macrophages, and have a matrix chemistry rich in hyaluronans, minimally sulfated proteoglycans, fetal collagens, and laminin. The microenvironment furnishes key signals driving HpSC activation and differentiation. Newly discovered third niches are pericentral within hepatic acini, contain Axin2+ unipotent hepatocytic progenitors linked on their lateral borders to endothelia forming the central vein, and contribute to normal turnover of mature hepatocytes. Their relationship to the other stem/progenitors is undefined. Stem/progenitor niches have important implications in regenerative medicine for the liver and biliary tree and in pathogenic processes leading to diseases of these tissues.

From the Bone Marrow to the Thymic Niche

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5123-5123
Author(s):  
Sandrine Susini ◽  
Séverine Mouraud ◽  
Elodie Elkaim ◽  
Julien Roullier ◽  
Sonia Luce ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Epithelial Cells ◽  
Progenitor Cells ◽  
Chemokine Receptors ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Adult Life ◽  
Thymic Epithelial Cells

Abstract To generate T cells throughout adult life, the thymus must import hematopoietic progenitor cells from the bone marrow via the blood. The cellular and molecular mechanisms governing the circulation of thymus-seeding progenitor cells are well characterized in mice but not in humans. The aim of the present study was to characterize the molecular mechanisms and cellular components involved in thymus colonization by lymphoid progenitors (CD34+/CD10+/CD7-/CD24-) and the early steps of thymopoiesis under physiological conditions in humans. Our results demonstrate that circulating lymphoid progenitor cells express CCR9 and CXCR4 chemokine receptors, VLA-4, VLA-5 and VLA-6 integrins and PSGL-1 and CD44 adhesion molecules. We used in vitro migration and adhesion assays to validate the functional status of these markers. As in the mouse, human circulating progenitor cells enter the thymus at the corticomedullary junction (CMJ). Once in the thymus, crosstalk with thymic epithelial cells causes the circulating progenitors to commit to the T-cell differentiation pathway. In order to characterize thymic niches and interactions between circulating progenitors and the thymic stroma, we undertook a chemokine/chemokine-receptor-focused gene expression analysis of sorted lymphoid progenitor cells and CMJ epithelial cells (based on the expression of EpCAM and Delta-like-4). We observed an unexpected gene expression profile for chemokines and chemokine regulators in thymus-seeding CD34+/CD10+/CD7-/CD24- cells and epithelial cells at the CMJ. The present results should help us to highlight candidate genes involved in the early steps of human thymopoiesis. Disclosures No relevant conflicts of interest to declare.

Increased TSLP availability restores T- and B-cell compartments in adult IL-7–deficient mice

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 3862-3870 ◽  
Author(s):  
Stephane Chappaz ◽  
Lukas Flueck ◽  
Andrew G. Farr ◽  
Antonius G. Rolink ◽  
Daniela Finke
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cell ◽  
Progenitor Cells ◽  
Hematopoietic Progenitor Cells ◽  
Fetal Life ◽  
Hematopoietic Progenitor ◽  
Interleukin 7 ◽  
Deficient Mice

AbstractInterleukin 7 (IL-7) plays a crucial role in adult lymphopoiesis, while in fetal life its effect can be partially compensated by TSLP. Whether adult hematopoietic progenitor cells are unresponsive to TSLP or whether TSLP is less available in adult microenvironments is still a matter of debate. Here, we show that increased TSLP availability through transgene (Tg) expression fully restored lymphopoiesis in IL-7–deficient mice: it rescued B-cell development, increased thymic and splenic cellularities, and restored double-negative (DN) thymocytes, αβ and γδ T-cell generation, and all peripheral lymphoid compartments. Analysis of bone marrow chimeras demonstrated that hematopoietic progenitor cells from adult wild-type mice efficiently differentiated toward B- and T-cell lineages in lethally irradiated IL-7 deficient mice provided TSLP Tg was expressed in these mice. In vitro, TSLP promoted the differentiation of uncommitted adult bone marrow progenitors toward B and T lineages and the further differentiation of DN1 and DN2 thymocytes. Altogether, our results show that adult hematopoietic cells are TSLP responsive and that TSLP can sustain long-term adult lymphopoiesis.

Mucin-producing cholangiocarcinoma might derive from biliary tree stem/progenitor cells located in peribiliary glands

Hepatology ◽  
2012 ◽  
Vol 55 (6) ◽  
pp. 2041-2042 ◽  
Author(s):  
Vincenzo Cardinale ◽  
Yunfang Wang ◽  
Guido Carpino ◽  
Lola M. Reid ◽  
Eugenio Gaudio ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Biliary Tree ◽  
Peribiliary Glands ◽  
Tree Stem

scholarly journals Tutorial Review for Understanding of Cholangiopathy

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Yasuni Nakanuma
Keyword(s):  
Epithelial Cells ◽  
Bile Ducts ◽  
Biliary Tree ◽  
Special Issue ◽  
Anatomy And Physiology ◽  
Biliary Epithelial Cells ◽  
Extrahepatic Bile Ducts ◽  
Bile Duct Damage ◽  
Peribiliary Glands ◽  
Extrahepatic Biliary Tree

The biliary tree consists of intrahepatic and extrahepatic bile ducts and is lined by biliary epithelial cells (or cholangiocytes). There are also peribiliary glands around the intrahepatic large bile ducts and extrahepatic bile ducts. The biliary tree is a conduit of bile secreted by hepatocytes and biliary epithelial cells and also of the peribiliary glands and has several physiological roles. A number of diseases affect mainly the intrahepatic and extrahepatic biliary tree, and, in this special issue, these cholangiopathies are reviewed in detail with respect to genetics, pathogenesis, and pathology. In this paper, the anatomy and physiology of the biliary tree, basic injuries to biliary epithelial cells from stress and bile duct damage, and representative cholangiopathies are briefly reviewed.

scholarly journals Vav1 Sustains the In Vitro Differentiation of Normal and Tumor Precursors to Insulin Producing Cells Induced by all-Trans Retinoic Acid (ATRA)

2020 ◽  
Author(s):  
Federica Brugnoli ◽  
Silvia Grassilli ◽  
Vincenzo Cardinale ◽  
Guido Carpino ◽  
Eugenio Gaudio ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Biliary Tree ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Approaches ◽  
Β Cells ◽  
Haematopoietic Cells ◽  
Insulin Producing Cells ◽  
All Trans Retinoic Acid ◽  
And Function

Abstract All-trans retinoic acid (ATRA) promotes the development and the function of insulin producing cells and induces partial differentiation of pancreatic tumor cells. A number of evidences clearly indicate that the ATRA mediated signaling may have a substantial role in therapeutic approaches based on restoration of functional β-cells. Among the proteins up-regulated by ATRA, Vav1 is involved in maturation and function of haematopoietic cells and is essential for retinoids induced differentiation of tumor promyelocytes. The presence of Vav1 in solid tissues, including pancreas, is considered ectopic and no role in the differentiation of human epithelial cells has so far been described. We demonstrated here that Vav1 sustains the maturation to β-cells of the normal precursors human Biliary Tree Stem/progenitor Cells (hBTSCs) induced by a differentiation medium containing ATRA and that, in the mature normal pancreas, insulin-producing cells express variable levels of Vav1. Using pancreatic ductal adenocarcinoma (PDAC)-derived cells, we also revealed that the ATRA induced up-modulation of Vav1 is essential for the retinoid-induced trans-differentiation of neoplastic cells into insulin producing cells. The results of this study identify Vav1 as crucial molecule in ATRA induced maturation of insulin producing cells and suggest this protein as a marker for new strategies ended to restore functional β-cells.

scholarly journals Cholest-4,6-Dien-3-One Promote Epithelial-To-Mesenchymal Transition (EMT) in Biliary Tree Stem/Progenitor Cell Cultures In Vitro

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1443
Author(s):  
Lorenzo Nevi ◽  
Daniele Costantini ◽  
Samira Safarikia ◽  
Sabina Di Matteo ◽  
Fabio Melandro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Epithelial To Mesenchymal Transition ◽  
Biliary Tree ◽  
Telomerase Activity ◽  
Mesenchymal Transition ◽  
Peribiliary Glands ◽  
Emt Markers ◽  
Tree Stem

Human biliary tree stem/progenitor cells (hBTSCs), reside in peribiliary glands, are mainly stimulated by primary sclerosing cholangitis (PSC) and cholangiocarcinoma. In these pathologies, hBTSCs displayed epithelial-to-mesenchymal transition (EMT), senescence characteristics, and impaired differentiation. Here, we investigated the effects of cholest-4,6-dien-3-one, an oxysterol involved in cholangiopathies, on hBTSCs biology. hBTSCs were isolated from donor organs, cultured in self-renewal control conditions, differentiated in mature cholangiocytes by specifically tailored medium, or exposed for 10 days to concentration of cholest-4,6-dien-3-one (0.14 mM). Viability, proliferation, senescence, EMT genes expression, telomerase activity, interleukin 6 (IL6) secretion, differentiation capacity, and HDAC6 gene expression were analyzed. Although the effect of cholest-4,6-dien-3-one was not detected on hBTSCs viability, we found a significant increase in cell proliferation, senescence, and IL6 secretion. Interestingly, cholest-4.6-dien-3-one impaired differentiation in mature cholangiocytes and, simultaneously, induced the EMT markers, significantly reduced the telomerase activity, and induced HDAC6 gene expression. Moreover, cholest-4,6-dien-3-one enhanced bone morphogenic protein 4 (Bmp-4) and sonic hedgehog (Shh) pathways in hBTSCs. The same pathways activated by human recombinant proteins induced the expression of EMT markers in hBTSCs. In conclusion, we demonstrated that chronic exposition of cholest-4,6-dien-3-one induced cell proliferation, EMT markers, and senescence in hBTSC, and also impaired the differentiation in mature cholangiocytes.

Human thymic epithelial cells maintain long-term survival of clonogenic myeloid and erythroid progenitor cells in vitro

2000 ◽  
Vol 111 (1) ◽  
pp. 363-370 ◽  
Author(s):  
Katsuto Takenaka ◽  
Mine Harada ◽  
Tomoaki Fujisaki ◽  
Koji Nagafuji ◽  
Shinichi Mizuno ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Progenitor Cells ◽  
Thymic Epithelial Cells ◽  
Erythroid Progenitor ◽  
Term Survival ◽  
Long Term Survival ◽  
Erythroid Progenitor Cells
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