Conversion of Terminally Committed Hepatocytes to Culturable Bipotent Progenitor Cells with Regenerative Capacity

Katsuda, Takeshi; Kawamata, Masayuki; Hagiwara, Kenta; Takahashi, Ryou U.; Yamamoto, Yusuke; Camargo, Fernando D.; Ochiya, Takahiro

doi:10.1016/j.stem.2016.10.007

Cited by 192 publications

(219 citation statements)

References 34 publications

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“…9G). A recent study has shown the conversion of terminally differentiated hepatocytes to bipotent AFP‐positive HPCs with regenerative capacity by adding a chemical cocktail to the culture media 42. It is therefore possible that the AFP‐expressing immature hepatocytes observed in the present study acquire the ability to differentiate into both hepatocytes and cholangiocytes in certain experimental conditions.…”

Section: Discussionmentioning

confidence: 73%

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Nakano

Nakao

Sumiyoshi

et al. 2017

Hepatology Communications

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The liver is well known to possess high regenerative capacity in response to partial resection or tissue injury. However, liver regeneration is often impaired in the case of advanced liver fibrosis/cirrhosis when mature hepatocytes can hardly self‐proliferate. Hepatic progenitor cells have been implicated as a source of hepatocytes in regeneration of the fibrotic liver. Although alpha‐fetoprotein (AFP) is known as a clinical marker of progenitor cell induction in injured/fibrotic adult liver, the origin and features of such AFP‐producing cells are not fully understood. Here, we demonstrate a unique and distinct AFP‐expressing cell population that is induced by the Jagged1/Notch2 signal in murine fibrotic liver. Following repeated carbon tetrachloride injections, a significant number of AFP‐positive cells with high proliferative ability were observed along the fibrous septa depending on the extent of liver fibrosis. These AFP‐positive cells exhibited features of immature hepatocytes that were stained positively for hepatocyte‐lineage markers, such as albumin and hepatocyte nuclear factor 4 alpha, and a stem/progenitor cell marker Sox9. A combination of immunohistological examination of fibrotic liver tissues and coculture experiments with primary hepatocytes and hepatic stellate cells indicated that increased Jagged1 expression in activated hepatic stellate cells stimulated Notch2 signaling and up‐regulated AFP expression in adjacent hepatocytes. The mobilization and proliferation of AFP‐positive cells in fibrotic liver were further enhanced after partial hepatectomy, which was significantly suppressed in Jagged1‐conditional knockout mice. Finally, forced expression of the intracellular domain of Notch2 in normal liver induced a small number of AFP‐expressing hepatocytes in vivo. Conclusion: Insight is provided into a novel pathophysiological role of Jagged1/Notch2 signaling in the induction of AFP‐positive cells in fibrotic liver through the interaction between hepatocytes and activated hepatic stellate cells. (Hepatology Communications 2017;1:215‐229)

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Section: Discussionmentioning

confidence: 73%

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Nakano

Nakao

Sumiyoshi

et al. 2017

Hepatology Communications

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“…If similar protocols could be established using human hepatocytes, this offers an additional source for HLCs for use in HT. Furthermore, the bipotent properties of CLiPs suggest that they could be used to tackle diseases related to the biliary tree as well as the liver [68]. …”

Section: Alternative Cell Sources For Hepatocyte Transplantationmentioning

confidence: 99%

Hepatocyte transplantation and advancements in alternative cell sources for liver-based regenerative medicine

et al. 2018

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Human hepatocyte transplantation has been actively perused as an alternative to liver replacement for acute liver failure and liver-based metabolic defects. Current challenges in this field include a limited cell source, reduced cell viability following cryopreservation and poor engraftment of cells into the recipient liver with consequent limited life span. As a result, alternative stem cell sources such as pluripotent stem cells, fibroblasts, hepatic progenitor cells, amniotic epithelial cells and mesenchymal stem/stromal cells (MSCs) can be used to generate induced hepatocyte like cells (HLC) with each technique exhibiting advantages and disadvantages. HLCs may have comparable function to primary human hepatocytes and could offer patient-specific treatment. However, long-term functionality of transplanted HLCs and the potential oncogenic risks of using stem cells have yet to be established. The immunomodulatory effects of MSCs are promising, and multiple clinical trials are investigating their effect in cirrhosis and acute liver failure. Here, we review the current status of hepatocyte transplantation, alternative cell sources to primary human hepatocytes and their potential in liver regeneration. We also describe recent clinical trials using hepatocytes derived from stem cells and their role in improving the phenotype of several liver diseases.

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“…Conditions have recently been described to achieve long-term culture of bi-potent liver progenitor cells acquired from liver tissue, which form organoids that are genetically-stable in vitro and appropriately express biliary markers [45]. Even more recently, a cocktail of small molecules has been published that have the potential to convert mature hepatocytes into bipotent chemically-induced liver progenitor cells with the capacity to differentiate into both mature hepatocytes and biliary epithelial cells [46]. Indeed, Katsuda et.…”

Section: Functional Modeling Of Alagille Syndromementioning

confidence: 99%

“…al . were able to show that these cells are able to repopulate chronically-injured liver tissue [46]. Thus far, these experiments have been done only in rat and mouse, and it remains to be seen whether human hepatocytes are chemically-susceptible to this conversion.…”

Section: Functional Modeling Of Alagille Syndromementioning

confidence: 99%

Alagille Syndrome: Genetics and Functional Models

Gilbert

Spinner

2017

Curr Pathobiol Rep

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Purpose of review We review the genetics of the autosomal dominant, multi-system disorder, Alagille syndrome and provide a summary on how current functional models and emerging biotechnologies are equipped to guide scientists towards novel therapies. The importance of haploinsufficiency as a disease mechanism will be underscored throughout this discussion. Recent findings Alagille syndrome, a human disorder affecting the liver, heart, vasculature, kidney, and other systems, is caused by mutations in the Notch signaling pathway ligand, Jagged1 (JAG1) or the receptor, NOTCH2. Current advances in animal modeling, in vitro cell culture, and human induced pluripotent stem cells, provide new opportunities in which to study disease mechanisms and manifestations. Summary We anticipate that the availability of innovative functional models will allow scientists to test new gene therapies or small molecule treatments in physiologically-relevant systems. With these advances, we look forward to the development of new methods to help Alagille syndrome patients.

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Conversion of Terminally Committed Hepatocytes to Culturable Bipotent Progenitor Cells with Regenerative Capacity

Cited by 192 publications

References 34 publications

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Hepatocyte transplantation and advancements in alternative cell sources for liver-based regenerative medicine

Alagille Syndrome: Genetics and Functional Models

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