Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of <i>Hnf-4−/−</i> embryos

Duncan, Stephen A.; Nagy, András; Chan, Wendy

doi:10.1242/dev.124.2.279

Cited by 274 publications

(7 citation statements)

References 46 publications

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“…4, A and B) (7,9). Although most MERVL-proximal genes are poorly characterized so far, we found a few genes that mediate important cellular events in pre-implantation development, including Hnf4a, which regulates visceral endoderm differentiation (49), and Usp17lc (Dub-2), which affects the development of the trophectoderm (50). Taken together, these findings suggest the possibility that ERVs, while traditionally viewed as evolutionary remnants of invading foreign DNA sequences, could have important yet unrecognized developmental functions.…”

Section: Discussionmentioning

confidence: 83%

Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells

Choi¹,

Lin²,

Risso³

et al. 2017

Science

137

133

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Embryonic stem cells and induced pluripotent stem cells have pluripotent developmental potential, efficiently giving rise to all embryonic cell types, but rarely extraembryonic lineages (1). Here, we identify a microRNA miR-34a, whose deficiency in mouse pluripotent stem cells expands their developmental potential to generate both embryonic and extra-embryonic lineages in vitro and in vivo. miR-34a−/− pluripotent stem cells with this bidirectional cell fate potential resemble totipotent 2-cell (2C) blastomeres not only in their cell fate potential, but also in the key molecular signature, namely a strong induction of the MuERV-L (MERVL) family of murine endogenous retroviruses (ERVs). miR-34a represses MERVL expression through transcriptional regulation, at least in part, by repressing the transcription factor GATA-binding protein 2 (Gata2). Consistently, the miR-34a/Gata2 pathway restricts the acquisition of bidirectional cell fate potential in pluripotent stem cells. Altogether, our findings provide vital insights into the complex molecular network that defines and restrict the developmental potential of pluripotent stem cells.

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Section: Discussionmentioning

confidence: 83%

Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells

Choi¹,

Lin²,

Risso³

et al. 2017

Science

137

133

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“…Indeed, the transduction efficiency of the pHNF3β-FMSN(þ) complex was slightly lower than that of the pHNF3β-Lipofectamine 2000 complex (Figure S16). Importantly, after induction of the hepatic differentiation for 15 days, the endogenous mRNA-expression levels of hepatocyte nuclear factor 4R (HNF4R; a specific visceral-endoderm gene), 84 albumin (ALB; a specific liver protein), and R-1-antitrypsin (AAT; a plasma serine protease inhibitor of liver) 85 were also up-regulated at iPSC-Heps treated with pHNF3β-FMSN(þ), as compared with the control groups (Figure 8b). The mRNA-expression levels of AML12, a mouse hepatocyte cell line, 86 were included for reference in Figure 8b.…”

Section: Resultsmentioning

confidence: 99%

Nonviral Cell Labeling and Differentiation Agent for Induced Pluripotent Stem Cells Based on Mesoporous Silica Nanoparticles

et al. 2013

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The generation of induced pluripotent stem cells (iPSCs) is an innovative personalized-regenerative technology, which can transform own-self somatic cells into embryonic stem (ES)-like cells, which have the potential to differentiate into all cell types of three dermal lineages. However, how to quickly, efficiently, and safely produce specific-lineage differentiation from pluripotent-state cells and iPSCs is still an open question. The objective of the present study was to develop a platform of a nonviral gene delivery system of mesoporous silica nanoparticles (MSNs) to rapidly generate iPSC-derived definitive-lineage cells, including endodermal-differentiated cells. We also evaluated the feasibility and efficiency of FITC-conjugated MSNs (FMSNs) for labeling of iPSCs and utilized the multifunctional properties of FMSNs for a suitable carrier for biomolecule delivery. We showed that FMSNs of various surface charges could be efficiently internalized by iPSCs without causing cytotoxicity. The levels of reactive oxygen species and pluripotent status, including in vitro stemness signatures and in vivo teratoma formation, remained unaltered. Notably, positive-charged FMSN enhanced cellular uptake efficiency and retention time. Moreover, when using positive-charged FMSN to deliver hepatocyte nuclear factor 3β (HNF3β) plasmid DNA (pDNA), the treated iPSCs exhibited significantly improved definitive endoderm formation and further quickly differentiated into hepatocyte-like cells with mature functions (low-density lipoprotein uptake and glycogen storage) within 2 weeks in vitro. Double delivery of pHNF3β further improved mRNA expression levels of liver-specific genes. These findings reveal the multiple advantages of FMSNs to serve as ideal vectors not only for stem cell labeling but also for safe gene delivery to promote the production of hepatocyte-like cells from iPSCs.

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“…[ 13 ] HNF4α is a master transcription factor for hepatocyte differentiation, which regulates genes responsible for liver function, including lipoprotein metabolism (Figure S2 ). [ 24 , 25 , 26 , 27 , 28 ] The dysregulation of HNF4α leads to the dedifferentiation of hepatocytes and clinical presentation of liver failure. RNA‐sequencing analyses suggest that both LCAT and LIPC mRNA levels were associated with the dysregulation of HNF4α transcription and disease severity of AH.…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol‐associated hepatitis

Pérez-Matos

Argemí

et al. 2021

Hepatology

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Background and Aims: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcoholassociated hepatitis (AH) and interrogate the biology behind its formation. Approach and Results:We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z.

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Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4−/− embryos

Cited by 274 publications

References 46 publications

Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells

Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells

Nonviral Cell Labeling and Differentiation Agent for Induced Pluripotent Stem Cells Based on Mesoporous Silica Nanoparticles

Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol‐associated hepatitis

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