Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver

Heo, Jeonghoon; Factor, Valentina M.; Uren, Tania; Takahama, Yasushi; Lee, Ju Seog; Major, Marian E.; Thorgeirsson, Snorri S.

doi:10.1002/hep.21441

Cited by 133 publications

(112 citation statements)

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“…Albumin-positive WT cells clustered in groups adjacent to regions of spontaneously differentiated beating cardiomyocytes, a phenomenon previously reported to occur during in vitro hepatocyte differentiation. 28,29 In contrast, Lats2 À / À cells displayed only background albumin staining (Figure 4c), and no beating cells were observed. Hence, Lats2 is necessary for the full Teratomas are benign tumors characterized by an intrinsic ability to yield all three germ layers.…”

Section: Resultsmentioning

confidence: 95%

Lats2 is critical for the pluripotency and proper differentiation of stem cells

et al. 2014

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Differentiation is a highly controlled process essential for embryonic and adult development. Moreover, disruption of proper differentiation is often associated with human diseases, including cancer. We analyzed the involvement of the tumor-suppressor Lats2 in mouse embryonic stem cell (mESC) pluripotency and differentiation, and report that mESCs lacking Lats2 are unable to sustain stemness and are not able to initiate and coordinate developmental transcriptional programs. Lats2 À / À mESCs retain bivalent 'poised' chromatin marks on developmental genes and exhibit germ layer ambiguity both in vitro and in vivo. Importantly, in coordinating proper germ layer specification, Lats2 engages in a feedback loop with another tumor suppressor, p53.

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Section: Resultsmentioning

confidence: 95%

Lats2 is critical for the pluripotency and proper differentiation of stem cells

et al. 2014

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“…It is noteworthy that some RIP-Cre lines themselves show impaired glucose tolerance. 22 Therefore, in these glucose tolerance and insulin secretion experiments, we included both RIP-Cre and heterozygous F/ϩ/ Cre mice as control, neither of which showed a significant difference compared with wild-type or Zbtb20 flox/flox control ( Figure 3C and E, and data not shown). These were consistent with previous reports that this RIP-Cre line has normal glucose tolerance.…”

Section: Ablation Of Zbtb20 In ␤ Cells Results In Glucose Intolerancementioning

confidence: 99%

The Zinc Finger Protein ZBTB20 Regulates Transcription of Fructose-1,6-Bisphosphatase 1 and β Cell Function in Mice

et al. 2012

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BACKGROUND & AIMS:Fructose-1,6-bisphosphatase (FBP)-1 is a gluconeogenic enzyme that regulates glucose metabolism and insulin secretion in ␤ cells, but little is known about how its transcription is controlled. The zinc finger protein ZBTB20 regulates glucose homeostasis, so we investigated its effects on expression of FBP-1. METH-ODS: We analyzed gene expression using real-time reverse-transcription polymerase chain reaction, immunoblotting, and immunohistochemistry. We generated mice with ␤ cell-specific disruption of Zbtb20 using Cre/LoxP technology. Expression of Zbtb20 in ␤ cells was reduced using small interfering RNAs, and promoter occupancy and transcriptional regulation were analyzed by chromatin immunoprecipitation and reporter assays. RESULTS: ZBTB20 was expressed at high levels by ␤ cells and other endocrine cells in islets of normal mice; expression levels were reduced in islets from diabetic db/db mice. Mice with ␤ cell-specific knockout of Zbtb20 had normal development of ␤ cells but had hyperglycemia, hypoinsulinemia, glucose intolerance, and impaired glucose-stimulated insulin secretion. Islets isolated from these mice had impaired glucose metabolism, adenosine triphosphate production, and insulin secretion after glucose stimulation in vitro, although insulin secretion returned to normal levels in the presence of KCl. ZBTB20 knockdown with small interfering RNAs impaired glucose-stimulated insulin secretion in the ␤ cell line MIN6. Expression of Fbp1 was up-regulated in ␤ cells with ZBTB20 knockout or knockdown; impairments to glucose-stimulated insulin secretion were restored by inhibition of FBPase activity. ZBTB20 was recruited to the Fbp1 promoter and repressed its transcription in ␤ cells. CONCLUSIONS: The transcription factor ZBTB20 regulates ␤ cell function and glucose homeostasis in mice. It might be a therapeutic target for type 2 diabetes mellitus.

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“…17,18) The in vitro approaches involve the formation of embryoid bodies (EBs) to mimic the inductive microenvironment required for liver organogenesis [19][20][21] and treatment with specific growth factors and cytokines critical for hepatic differentiation.…”

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confidence: 99%

“…16) After birth, CYP7A1 increases several-fold with age both at the enzyme activity level and the mRNA level. 17,18) The in vitro approaches involve the formation of embryoid bodies (EBs) to mimic the inductive microenvironment required for liver organogenesis [19][20][21] and treatment with specific growth factors and cytokines critical for hepatic differentiation. 22) At present, culture systems for ES cells have mainly used gelatin-or collagen-coated plates as the matrix for the maintenance of cells in an undifferentiated state and differentiation.…”

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confidence: 99%

Differentiation of Monkey Embryonic Stem Cells into Hepatocytes and mRNA Expression of Cytochrome P450 Enzymes Responsible for Drug Metabolism: Comparison of Embryoid Body Formation Conditions and Matrices

Momose

Matsunaga

Murai

et al. 2009

Biological & Pharmaceutical Bulletin

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Examination of drug metabolism using human hepatocytes is important in the early stages of drug development. However, primary human hepatocytes are short-lived and cannot be maintained in culture over the long term. Considerable donor-dependent variations are also problematic. Human embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of blastocysts and are capable of differentiating into three embryonic germ layers and germ cells.1) The cells apparently differentiate into various types of mature cells, and are thereby an attractive source for routine access to large numbers of cells that can be used for the development of candidate drug-screening strategies replacing primary cells.2) However, ethical considerations have limited the availability of human ES cells. The phenotype of human ES cells is known to be similar to that of monkey ES cells but differs from that of mouse ES cells with regard to morphology, response to leukemia inhibitory factor, and gene expression patterns. 1,[3][4][5] Research using monkey ES cells is considered to be useful for investigation of differentiation mechanisms in primate ES cells and models of human ES cells. Recently, it has been shown that monkey ES cells can be differentiated into various cell types-including neurons, hematopoietic cells, and pancreatic cells-using growth factors. [6][7][8] Hepatocytes derived from monkey ES cells may be useful for pharmacokinetic examinations such as induction of drug metabolism enzymes and interactions of candidate drugs. To date however, there have been few reported studies describing the differentiation of monkey ES cells into hepatocytes. 9,10) After the emergence of the liver bud from the developing gut tube, the level of hepatic maturation is characterized by the expression of liver-and stage-specific genes. For example, alfa-fetoprotein (AFP) is an early hepatic marker, expressed by hepatoblasts in the liver bud until birth.11,12) The synthesis of AFP decreases dramatically after birth and only trace amounts are expressed in the adult liver. In contrast, albumin (ALB), the most abundant protein synthesized by hepatocytes, is initially expressed at lower levels in early fetal hepatocytes but this increases as the hepatocytes mature, reaching a maximum in adult hepatocytes. 13,14) The mRNA expression of cytochrome P450 7A1 (CYP7A1) which is a rate-limiting enzyme in the conversion of cholesterol to bile acids in liver 15) is detected in fetal liver of third trimester of pregnancy.16) After birth, CYP7A1 increases several-fold with age both at the enzyme activity level and the mRNA level. 17,18) The in vitro approaches involve the formation of embryoid bodies (EBs) to mimic the inductive microenvironment required for liver organogenesis [19][20][21] and treatment with specific growth factors and cytokines critical for hepatic differentiation.22) At present, culture systems for ES cells have mainly used gelatin-or collagen-coated plates as the matrix for the maintenance of cells in an undifferentiated state an...

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Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver

Cited by 133 publications

References 35 publications

Lats2 is critical for the pluripotency and proper differentiation of stem cells

Lats2 is critical for the pluripotency and proper differentiation of stem cells

The Zinc Finger Protein ZBTB20 Regulates Transcription of Fructose-1,6-Bisphosphatase 1 and β Cell Function in Mice

Differentiation of Monkey Embryonic Stem Cells into Hepatocytes and mRNA Expression of Cytochrome P450 Enzymes Responsible for Drug Metabolism: Comparison of Embryoid Body Formation Conditions and Matrices

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