Human duodenal submucosal glands contain a defined stem/progenitor subpopulation with liver-specific regenerative potential

Cardinale, Vincenzo; Carpino, Guido; Overi, Diletta; Safarikia, Samira; Zhang, Wencheng; Kanke, Matt; Franchitto, Antonio; Costantini, D.; Riccioni, Olga; Chiappetta, Michele Francesco; Onori, Paolo; Franchitto, Matteo; Bini, Simone; Hung, Yu‐Han; Lai, Quirino; Zizzari, Ilaria Grazia; Nuti, Marianna; Nicoletti, Carmine; Checquolo, Saula; Magno, Laura Di; Giuli, Maria Valeria; Rossi, Massimo; Sethupathy, Praveen; Reíd, Lola M.; Alvaro, Domenico; Gaudio, Eugenio

doi:10.1016/j.jhep.2022.08.037

Cited by 9 publications

(12 citation statements)

References 29 publications

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“…Extensive characterizations of the human network have offered guides of isolation and management, to the candidate phenotypic traits of the hepato/pancreatic co-stem/progenitors and of the network 5 , 26 , 31 – 35 . In humans, the complex network is comprised of stem cells in extramural PBGs (tethered to the outside of large ducts that are ≥300 μm), at the bottoms (near the bile duct centers) of intramural PBGs (within the duct walls), and in duodenal glands, also called Brunner’s Glands, in the submucosa of the duodenum 5 , 29 – 33 , 36 . The extramural PBGs 30 , 32 and Brunner’s Glands 34 , 36 contain the most primitive of the stem cell populations identified and have anatomical connections to the intramural population 5 , 32 .…”

Section: Introductionmentioning

confidence: 99%

“…In humans, the complex network is comprised of stem cells in extramural PBGs (tethered to the outside of large ducts that are ≥300 μm), at the bottoms (near the bile duct centers) of intramural PBGs (within the duct walls), and in duodenal glands, also called Brunner’s Glands, in the submucosa of the duodenum 5 , 29 – 33 , 36 . The extramural PBGs 30 , 32 and Brunner’s Glands 34 , 36 contain the most primitive of the stem cell populations identified and have anatomical connections to the intramural population 5 , 32 . Key known functions of the biliary tree and pancreatic ducts are as a conduit for bile from the liver and for digestive enzymes from the pancreas, and, discovered within the last decade, as a reservoir of multiple stem/progenitor subpopulations contributing throughout life to biliary, hepatic and pancreatic regenerative processes both in quiescent states and in diseased ones 5 , 29 – 31 , 37 , 38 .…”

Section: Introductionmentioning

confidence: 99%

“…There is also a proximal to distal axis of maturation from the duodenum via the extrahepatic and intrahepatic (or intrapancreatic) biliary tree to the organ (liver or pancreas) in which the radial axes of lineages in ducts near to the liver contain cells that mature to have hepatic traits versus those in ducts near to or in the pancreas, acquire pancreatic traits. Therefore, the regenerative processes for the liver and the pancreas are ongoing throughout life via the maturation of cells from stem cell crypts throughout the biliary tree 5 , 31 , 32 , 36 , 39 .…”

Section: Introductionmentioning

confidence: 99%

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A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans

Zhang

Wang

Lanzoni³

et al. 2023

npj Regen Med

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A network of co-hepato/pancreatic stem/progenitors exists in pigs and humans in Brunner’s Glands in the submucosa of the duodenum, in peribiliary glands (PBGs) of intrahepatic and extrahepatic biliary trees, and in pancreatic duct glands (PDGs) of intrapancreatic biliary trees, collectively supporting hepatic and pancreatic regeneration postnatally. The network is found in humans postnatally throughout life and, so far, has been demonstrated in pigs postnatally at least through to young adulthood. These stem/progenitors in vivo in pigs are in highest numbers in Brunner’s Glands and in PDGs nearest the duodenum, and in humans are in Brunner’s Glands and in PBGs in the hepato/pancreatic common duct, a duct missing postnatally in pigs. Elsewhere in PDGs in pigs and in all PDGs in humans are only committed unipotent or bipotent progenitors. Stem/progenitors have genetic signatures in liver/pancreas-related RNA-seq data based on correlation, hierarchical clustering, differential gene expression and principal component analyses (PCA). Gene expression includes representative traits of pluripotency genes (SOX2, OCT4), endodermal transcription factors (e.g. SOX9, SOX17, PDX1), other stem cell traits (e.g. NCAM, CD44, sodium iodide symporter or NIS), and proliferation biomarkers (Ki67). Hepato/pancreatic multipotentiality was demonstrated by the stem/progenitors’ responses under distinct ex vivo conditions or in vivo when patch grafted as organoids onto the liver versus the pancreas. Therefore, pigs are logical hosts for translational/preclinical studies for cell therapies with these stem/progenitors for hepatic and pancreatic dysfunctions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans

Zhang

Wang

Lanzoni³

et al. 2023

npj Regen Med

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“…Of course, HT also has adverse effects in specific clinical situations. During hepatocyte infusion in the portal vein, intrapleural, or peritoneal, some patients developed deadly mesenteric vein thrombosis [ 30 ] and non-lethal splenic vein thrombosis [ 57 ]. This shows that there is still room for improvement in hepatocyte delivery.…”

Section: Diverse Cell Sources and Therapeutic Sites For Cell Therapymentioning

confidence: 99%

Cell therapy in end-stage liver disease: replace and remodel

Chen

Wu³

et al. 2023

Stem Cell Res Ther

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Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient treatment for end-stage liver disease, its application has been limited by the scarcity of donor livers. The lack of acceptable donor organs implies that patients are at high risk while waiting for suitable livers. In this scenario, cell therapy has emerged as a promising treatment approach. Most of the time, transplanted cells can replace host hepatocytes and remodel the hepatic microenvironment. For instance, hepatocytes derived from donor livers or stem cells colonize and proliferate in the liver, can replace host hepatocytes, and restore liver function. Other cellular therapy candidates, such as macrophages and mesenchymal stem cells, can remodel the hepatic microenvironment, thereby repairing the damaged liver. In recent years, cell therapy has transitioned from animal research to early human studies. In this review, we will discuss cell therapy in end-stage liver disease treatment, especially focusing on various cell types utilized for cell transplantation, and elucidate the processes involved. Furthermore, we will also summarize the practical obstacles of cell therapy and offer potential solutions.

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“…[44][45][46][47][48] Further, epithelial cells lining the gallbladder and large bile ducts strongly express mRNAs encoding Indian hedgehog ligand in healthy adults 48 and expression of both Indian and Sonic hedgehog ligands increase significantly in interlobular bile ducts of diseased livers. 44,45,[47][48][49][50] These findings have led some investigators to propose that adult livers harbor a series of dynamic portal-based stem/progenitor compartments that modulate Hedgehog signaling to configure niche microenvironments and direct cell state transitions both to meet demands for cholangiocyte replacement in different segments of the biliary tree 46,51,52 and to restrict the biliary phenotype to liver epithelial cells in portal areas. 48 Hedgehog signaling generally promotes survival of biliary cells and increases proliferation of biliary stem/progenitor cells but it also gates progenitor differentiation and epithelial-mesenchymal state transitions in more mature liver epithelial cells.…”

Section: Biliary Diseasementioning

confidence: 99%

Hedgehog Signaling: Implications in Liver Pathophysiology

Dutta,

Jun,

et al. 2023

Semin Liver Dis

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The purpose of this review is to summarize current knowledge about the role of the Hedgehog signaling pathway in liver homeostasis and disease. Hedgehog is a morphogenic signaling pathway that is active in development. In most healthy tissues, pathway activity is restricted to stem cell and/or stromal cell compartments, where it enables stem cell self-renewal and tissue homeostasis. Aberrant over-activation of Hedgehog signaling occurs in many cancers, including hepatocellular and cholangio- carcinoma. The pathway is also activated transiently in stromal cells of injured tissues and orchestrates normal wound healing responses, including inflammation, vascular remodeling and fibrogenesis. In liver, sustained Hedgehog signaling in stromal cells plays a major role in the pathogenesis of cirrhosis. Hedgehog signaling was thought to be silenced in healthy hepatocytes. However, recent studies show that targeted disruption of the pathway in hepatocytes dysregulates lipid, cholesterol, and bile acid metabolism and promotes hepatic lipotoxicity, insulin resistance and senescence. Hepatocytes that lack Hedgehog activity also produce a secretome that activates Hedgehog signaling in cholangiocytes and neighboring stromal cells to induce inflammatory and fibrogenic wound healing responses that drive progressive fibrosis. In conclusion, Hedgehog signaling must be precisely controlled in adult liver cells in order to maintain liver health.

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Human duodenal submucosal glands contain a defined stem/progenitor subpopulation with liver-specific regenerative potential

Cited by 9 publications

References 29 publications

A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans

A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans

Cell therapy in end-stage liver disease: replace and remodel

Hedgehog Signaling: Implications in Liver Pathophysiology

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