Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration

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.

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Contribution of Resident Stem Cells to Liver and Biliary Tree Regeneration in Human Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms19102917 ◽

2018 ◽

Vol 19 (10) ◽

pp. 2917 ◽

Cited By ~ 20

Author(s):

Diletta Overi ◽

Guido Carpino ◽

Vincenzo Cardinale ◽

Antonio Franchitto ◽

Samira Safarikia ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Progenitor Cells ◽

Human Liver ◽

Progenitor Cell ◽

Biliary Tree ◽

Tree Regeneration ◽

Multipotent Stem Cells ◽

Resident Stem Cells ◽

Stem Cell Niches

Two distinct stem/progenitor cell populations of biliary origin have been identified in the adult liver and biliary tree. Hepatic Stem/progenitor Cells (HpSCs) are bipotent progenitor cells located within the canals of Hering and can be differentiated into mature hepatocytes and cholangiocytes; Biliary Tree Stem/progenitor Cells (BTSCs) are multipotent stem cells located within the peribiliary glands of large intrahepatic and extrahepatic bile ducts and able to differentiate into hepatic and pancreatic lineages. HpSCs and BTSCs are endowed in a specialized niche constituted by supporting cells and extracellular matrix compounds. The actual contribution of these stem cell niches to liver and biliary tree homeostatic regeneration is marginal; this is due to the high replicative capabilities and plasticity of mature parenchymal cells (i.e., hepatocytes and cholangiocytes). However, the study of human liver and biliary diseases disclosed how these stem cell niches are involved in the regenerative response after extensive and/or chronic injuries, with the activation of specific signaling pathways. The present review summarizes the contribution of stem/progenitor cell niches in human liver diseases, underlining mechanisms of activation and clinical implications, including fibrogenesis and disease progression.

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P107 HUMAN BILIARY TREE STEM/PROGENITOR CELLS (hbTSCS) FROM PERIBILIARY GLANDS (PBGS) OF ADULT LIVER DISPLAY IMMUNOMODULATORY PROPERTIES THROUGH Fas/Fas LIGAND INDUCED T-CELL LYMPHOCYTE APOPTOSIS

Journal of Hepatology ◽

10.1016/s0168-8278(14)60270-1 ◽

2014 ◽

Vol 60 (1) ◽

pp. S102

Author(s):

G. Carnevale ◽

M. Riccio ◽

V. Cardinale ◽

L. Gibelini ◽

S. De Biasi ◽

...

Keyword(s):

T Cell ◽

Progenitor Cells ◽

Fas Ligand ◽

Biliary Tree ◽

Lymphocyte Apoptosis ◽

Adult Liver ◽

Immunomodulatory Properties ◽

Peribiliary Glands ◽

Tree Stem

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Autocrine regulation of mesenchymal progenitor cell fates orchestrates tooth eruption

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1810200115 ◽

2018 ◽

Vol 116 (2) ◽

pp. 575-580 ◽

Cited By ~ 27

Author(s):

Akira Takahashi ◽

Mizuki Nagata ◽

Aditi Gupta ◽

Yuki Matsushita ◽

Tetsutaro Yamaguchi ◽

...

Keyword(s):

Progenitor Cells ◽

Progenitor Cell ◽

Tooth Eruption ◽

Cellular Heterogeneity ◽

Periodontal Ligament Cells ◽

Mesenchymal Progenitor Cell ◽

Tooth Root ◽

Mesenchymal Progenitor Cells ◽

Cell Fates ◽

Periodontal Attachment

Formation of functional skeletal tissues requires highly organized steps of mesenchymal progenitor cell differentiation. The dental follicle (DF) surrounding the developing tooth harbors mesenchymal progenitor cells for various differentiated cells constituting the tooth root–bone interface and coordinates tooth eruption in a manner dependent on signaling by parathyroid hormone-related peptide (PTHrP) and the PTH/PTHrP receptor (PPR). However, the identity of mesenchymal progenitor cells in the DF and how they are regulated by PTHrP-PPR signaling remain unknown. Here, we show that the PTHrP-PPR autocrine signal maintains physiological cell fates of DF mesenchymal progenitor cells to establish the functional periodontal attachment apparatus and orchestrates tooth eruption. A single-cell RNA-seq analysis revealed cellular heterogeneity of PTHrP+ cells, wherein PTHrP+ DF subpopulations abundantly express PPR. Cell lineage analysis using tamoxifen-inducible PTHrP-creER mice revealed that PTHrP+ DF cells differentiate into cementoblasts on the acellular cementum, periodontal ligament cells, and alveolar cryptal bone osteoblasts during tooth root formation. PPR deficiency induced a cell fate shift of PTHrP+ DF mesenchymal progenitor cells to nonphysiological cementoblast-like cells precociously forming the cellular cementum on the root surface associated with up-regulation of Mef2c and matrix proteins, resulting in loss of the proper periodontal attachment apparatus and primary failure of tooth eruption, closely resembling human genetic conditions caused by PPR mutations. These findings reveal a unique mechanism whereby proper cell fates of mesenchymal progenitor cells are tightly maintained by an autocrine system mediated by PTHrP-PPR signaling to achieve functional formation of skeletal tissues.

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Human biliary tree stem/progenitor cells (hBTSCs) from peribiliary glands (PBGs) of adult liver display immunomodulatory properties through Fas/Fas ligand induced T-cell lymphocyte apoptosis

Digestive and Liver Disease ◽

10.1016/j.dld.2014.01.069 ◽

2014 ◽

Vol 46 ◽

pp. e30

Author(s):

G. Carnevale ◽

M. Riccio ◽

V. Cardinale ◽

L. Gibelini ◽

S. De Biasi ◽

...

Keyword(s):

T Cell ◽

Progenitor Cells ◽

Fas Ligand ◽

Biliary Tree ◽

Lymphocyte Apoptosis ◽

Adult Liver ◽

Immunomodulatory Properties ◽

Peribiliary Glands ◽

Tree Stem

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Immunohistochemical demonstration of pancreatic α-amylase and trypsin in intrahepatic bile ducts and peribiliary glands

Hepatology ◽

10.1002/hep.1840140629 ◽

1991 ◽

Vol 14 (6) ◽

pp. 1129-1135 ◽

Cited By ~ 33

Author(s):

Tadashi Terada ◽

Yasuni Nakanuma

Keyword(s):

Bile Ducts ◽

Intrahepatic Bile Ducts ◽

Immunohistochemical Demonstration ◽

Peribiliary Glands

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Lectin binding of intrahepatic bile ducts and peribiliary glands in normal livers and hepatolithiasis.

The Tohoku Journal of Experimental Medicine ◽

10.1620/tjem.160.81 ◽

1990 ◽

Vol 160 (1) ◽

pp. 81-92 ◽

Cited By ~ 4

Author(s):

KATSUHIKO SAITO ◽

YASUNI NAKANUMA

Keyword(s):

Bile Ducts ◽

Lectin Binding ◽

Intrahepatic Bile Ducts ◽

Peribiliary Glands

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Administration of r-VEGF-A prevents hepatic artery ligation-induced bile duct damage in bile duct ligated rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00507.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. G307-G317 ◽

Cited By ~ 49

Author(s):

Eugenio Gaudio ◽

Barbara Barbaro ◽

Domenico Alvaro ◽

Shannon Glaser ◽

Heather Francis ◽

...

Keyword(s):

Bile Duct ◽

Hepatic Artery ◽

Bile Ducts ◽

Biliary Tree ◽

Hepatic Artery Ligation ◽

Artery Ligation ◽

Intrahepatic Bile Ducts ◽

Duct Ligation ◽

Liver Morphology ◽

Endothelial Growth Factor

The hepatic artery, through the peribiliary plexus, nourishes the intrahepatic biliary tree. During obstructive cholestasis, the nutritional demands of intrahepatic bile ducts are increased as a consequence of enhanced proliferation; in fact, the peribiliary plexus (PBP) displays adaptive expansion. The effects of hepatic artery ligation (HAL) on cholangiocyte functions during cholestasis are unknown, although ischemic lesions of the biliary tree complicate the course of transplanted livers and are encountered in cholangiopathies. We evaluated the effects of HAL on cholangiocyte functions in experimental cholestasis induced by bile duct ligation (BDL). By using BDL and BDL + HAL rats or BDL + HAL rats treated with recombinant-vascular endothelial growth factor-A (r-VEGF-A) for 1 wk, we evaluated liver morphology, the degree of portal inflammation and periductular fibrosis, microcirculation, cholangiocyte apoptosis, proliferation, and secretion. Microcirculation was evaluated using a scanning electron microscopy vascular corrosion cast technique. HAL induced in BDL rats 1) the disappearance of the PBP, 2) increased apoptosis and impaired cholangiocyte proliferation and secretin-stimulated ductal secretion, and 3) decreased cholangiocyte VEGF secretion. The effects of HAL on the PBP and cholangiocyte functions were prevented by r-VEGF-A, which, by maintaining the integrity of the PBP and cholangiocyte proliferation, prevents damage of bile ducts following ischemic injury.

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Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages

Journal of Anatomy ◽

10.1111/j.1469-7580.2011.01462.x ◽

2011 ◽

Vol 220 (2) ◽

pp. 186-199 ◽

Cited By ~ 127

Author(s):

Guido Carpino ◽

Vincenzo Cardinale ◽

Paolo Onori ◽

Antonio Franchitto ◽

Pasquale Bartolomeo Berloco ◽

...

Keyword(s):

Progenitor Cells ◽

Bile Ducts ◽

Biliary Tree ◽

In Situ Study ◽

Tree Stem

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Identification of a pancreatic stellate cell population with properties of progenitor cells: new role for stellate cells in the pancreas

Biochemical Journal ◽

10.1042/bj20081466 ◽

2009 ◽

Vol 421 (2) ◽

pp. 181-191 ◽

Cited By ~ 33

Author(s):

Eugenia Mato ◽

Maria Lucas ◽

Jordi Petriz ◽

Ramon Gomis ◽

Anna Novials

Keyword(s):

Progenitor Cells ◽

Cell Population ◽

Glucose Transporter ◽

Stellate Cell ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Diabetes Research ◽

Pancreatic Cell ◽

Cell Clusters ◽

Ultrastructural Studies

Numerous studies conducted in a diversity of adult tissues have shown that certain stem cells are characterized by the expression of a protein known as the ABCG2 transporter (where ABC is ATP- binding cassette). In the adult pancreas, although various multipotent progenitors have been proposed, the ABCG2 marker has only been detected in the so-called ‘side population’ (a primitive haematopoietic cell population with a multipotential capacity). In the present study we sought to identify new ABCG2+ pancreatic cell populations and to explore whether they exhibit the properties of progenitor cells. We isolated and expanded mitoxantrone-resistant cells from pancreata of lactating rats by drug selection. These cells were characterized and maintained in different stages of differentiation using several media ‘cocktails’ plus Matrigel™ (BD Biosciences). Differentiation was assessed by RT–PCR (reverse transcription–PCR), immunocytochemistry, electron microscopy and ELISA. The expanded cell population demonstrated a phenotype of PaSCs (pancreatic stellate cells). Spontaneous cell clusters occurred during cell expansion and they showed weak expression of the transcription factor Pdx1 (pancreatic and duodenal homeobox 1). Moreover, the presence of inductive factors in the Matrigel plus exendin-4 led to an increase in Pdx1 and endocrine genes, such as insulin, islet amyloid polypeptide, glucagon, the glucose transporter GLUT2, chromogranin A and the convertases PC1/3 and PC2 were also detected. Immunocytochemical analysis showed co-localization of insulin and C-peptide, whereas ultrastructural studies revealed the presence of granules. Insulin secretion from cell clusters was detected in the cell culture medium. We identified a population of PaSCs that express the ABCG2+ transporter and have the capacity to transdifferentiate into insulin-producing cells. Although the potential therapeutic application remains to be tested, PaSCs could represent a future option for insulin replacement in diabetes research.

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