Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver

Suzuki, Atsushi; Zheng, Yun‐Wen; Kaneko, Shin; Onodera, Masafumi; Fukao, Katashi; Nakauchi, Hiromitsu; Taniguchi, Hideki

doi:10.1083/jcb.200108066

Cited by 334 publications

(316 citation statements)

References 37 publications

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“…The key to the success of the transplantation was again that the mice had been pre-treated with retrorsine (blocking indigenous hepatocyte replication) and given courses of hepatocyte-destroying CCl 4 , both before and after cell transplantation. Clonogenic cells have also been isolated by Suzuki et al [56] from fetal mouse liver (ED13.5), on the basis of expressing the integrins α6 (CD49f) and β1 (CD29) but not c-kit, CD45 or Ter119 (erythroid precursor antigen). Designated 'hepatic colony-forming units in culture' (H-CFU-C), this sorting achieved a 35-fold enrichment of H-CFU-C over total fetal liver cells.…”

Section: Mr Alison Et Almentioning

confidence: 99%

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Alison

Islam

Lim

2008

The Journal of Pathology

201

149

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The worldwide shortage of donor livers to transplant end stage liver disease patients has prompted the search for alternative cell therapies for intractable liver diseases, such as acute liver failure, cirrhosis and hepatocellular carcinoma (HCC). Under normal circumstances the liver undergoes a low rate of hepatocyte 'wear and tear' renewal, but can mount a brisk regenerative response to the acute loss of two-thirds or more of the parenchymal mass. A body of evidence favours placement of a stem cell niche in the periportal regions, although the identity of such stem cells in rodents and man is far from clear. In animal models of liver disease, adopting strategies to provide a selective advantage for transplanted hepatocytes has proved highly effective in repopulating recipient livers, but the poor success of today's hepatocyte transplants can be attributed to the lack of a clinically applicable procedure to force a similar repopulation of the human liver. The activation of bipotential hepatic progenitor cells (HPCs) is clearly vital for survival in many cases of acute liver failure, and the signals that promote such reactions are being elucidated. Bone marrow cells (BMCs) make, at best, a trivial contribution to hepatocyte replacement after damage, but other BMCs contribute to the hepatic collagen-producing cell population, resulting in fibrotic disease; paradoxically, BMC transplantation may help alleviate established fibrotic disease. HCC may have its origins in either hepatocytes or HPCs, and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.

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Section: Mr Alison Et Almentioning

confidence: 99%

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Alison

Islam

Lim

2008

The Journal of Pathology

201

149

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“…To determine whether the ES-derived hepatic progenitor cells can differentiate into bile duct cells, they were cultured in Matrigel, previously shown to favor bile duct cell differentiation [Spagnoli et al, 1998;Suzuki et al, 2002]. The cells underwent morphological changes and their proliferation was reduced.…”

Section: In Vitro Differentiation Of Es-derived Hepatic Progenitor Cementioning

confidence: 99%

In vitro differentiation of hepatic progenitor cells from mouse embryonic stem cells induced by sodium butyrate

Zhou

Xiang

Shao

et al. 2006

J of Cellular Biochemistry

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Recently it was shown that embryonic stem (ES) cells could differentiate into hepatocytes both in vitro and in vivo, however, prospective hepatic progenitor cells have not yet been isolated and characterized from ES cells. Here we presented a novel 4-step procedure for the differentiation of mouse ES cells into hepatic progenitor cells and then hepatocytes. The differentiated hepatocytes were identified by morphological, biochemical, and functional analyses. The hepatic progenitor cells were isolated from the cultures after the withdrawal of sodium butyrate, which was characterized by scant cytoplasm, ovoid nuclei, the ability of rapid proliferation, expression of a series of hepatic progenitor cell markers, and the potential of differentiation into hepatocytes and bile duct-like cells under the proper conditions that favor hepatocyte and bile epithelial differentiation. The differentiation of hepatocytes from hepatic progenitor cells was characterized by a number of hepatic cell markers including albumin secretion, upregulated transcription of glucose-6-phophatase and tyrosine aminotransferase, and functional phenotypes such as glycogen storage. The results from our experiments demonstrated that ES cells could differentiate into a novel bipotential hepatic progenitor cell and mature into hepatocytes with typical morphological, phenotypic and functional characteristics, which provides an useful model for the studies of key events during early liver development and a potential source of transplantable cells for cell-replacement therapies.

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“…After evaluating a large panel of markers because no single antigen had been definitely validated (30), we observed that all of the cultured cells expressed the a6 and b1 integrins, fundamental in ensuring cell adhesion and clonality of hepatic progenitor cells (1,2). EpCAM and CD133 antigens were also expressed on freshly isolated L-EpPCs, but their reactivity progressively decreased as the cells matured, as also suggested by the gradual increase in CD166 and a1-antitrypsin positivity during culture.…”

Section: Discussionmentioning

confidence: 93%

“…Media were changed three times a week. LEnPCs and L-EpPCs were counted at each passage and, at the first and fifth passages, characterized for the expression of various markers (1,2,16,17,(19)(20)(21).…”

Section: In Vitro Cell Culturesmentioning

confidence: 99%

Simultaneous characterization of progenitor cell compartments in adult human liver

et al. 2009

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The human liver is a complex tissue consisting of epithelial, endothelial, hematopoietic, and mesenchymal elements that probably derive from multiple lineage-committed progenitors, but no comprehensive study aimed at identifying and characterizing intrahepatic precursors has yet been published. Cell suspensions for this study were obtained by enzymatic digestion of liver specimens taken from 20 patients with chronic liver disease and 13 multiorgan donors. Stem and progenitor cells were first isolated, amplified, and characterized ex vivo according to previously validated methods, and then optimized flow cytometry was used to assess their relative frequencies and characterize their immunophenotypes in the clinical specimens. Stem and progenitor cells committed to hematopoietic, endothelial, epithelial, and mesenchymal lineages were clearly identifiable in livers from both healthy and diseased subjects. Within the mononuclear liver cell compartment, epithelial progenitors [epithelial cell adhesion molecule (EpCAM) 1 / CD49f 1 /CD29 1 /CD45 2 ] accounted for 2.7-3.5% whereas hematopoietic (CD34 1 / CD45 1 ), endothelial [vascular endothelial growth factor-2 (KDR) 1 /CD146 1 /CD45 2 ], and mesenchymal [CD73 1 /CD105 1 /CD90 (Thy-1) 1 /CD45 2 ] stem cells and progenitors accounted for smaller fractions (0.02-0.6%). The patients' livers had higher percentages of hematopoietic and endothelial precursors than those of the donors. In conclusion, we identified and characterized precursors committed to four different lineages in adult human liver. We also optimized a flow cytometry approach that will be useful in exploring the contribution of these cells to the pathogenesis of liver disease. ' International Society for Advancement of CytometryKey terms stem and progenitor cells; human liver; flow cytometry ADULT human liver is a complex tissue consisting of epithelial, endothelial, hematopoietic, and mesenchymal elements. This supports the view that the intrahepatic stem and progenitor cell compartment probably consists of a heterogeneous pool with various molecular and functional markers. Studies characterizing hepatic stem cells and progenitors have so far mainly concentrated on the epithelial compartment, and generally used human fetal or rodent liver (1,2); only a few have identified and characterized the hematopoietic (3,4), endothelial (5), and mesenchymal lineages (6), although it is well known that their progenies are deeply involved in the pathogenesis of liver disease (7).Despite recent growth of interest in liver stem and progenitor cell research and great expectations concerning the potential of these cells in the field of regenerative medicine (8), we are unaware of comprehensive studies of the entire stem/progenitor cell pool. This could be due to the rare occurrence of these cells in liver tissue, and the possible overlap in the immunological profiles of the cells committed to different lineages (9-11), thus making their identification difficult.

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Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver

Cited by 334 publications

References 37 publications

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

In vitro differentiation of hepatic progenitor cells from mouse embryonic stem cells induced by sodium butyrate

Simultaneous characterization of progenitor cell compartments in adult human liver

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