Localized T3 production modifies the transcriptome and promotes the hepatocyte-like lineage in iPSC-derived hepatic organoidslineage in iPSC-derived hepatic organoids
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ABSTRACT:
PROVIDER: PRJNA1027474 | ENA |
REPOSITORIES: ENA
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Project description:Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here we studied human iPSC-derived hepatic organoids and identified a robust induction in DIO2 expression (the deiodinase that activates T4 to T3) that occurs in hepatoblasts. The surge in D2-T3 persists until the hepatoblasts differentiate into hepatocytes- or cholangiocytes-like cells, neither of which express DIO2. Preventing the induction of the D2-T3 signaling modified the expression of key transcription factors, decreased the number of hepatocyte-like cells by ~60%, and increased the number of cholangiocyte-like cells by ~55% without affecting the growth or the size of the mature liver organoid. Physiological levels of T3 could not fully restore the transition from hepatoblasts to mature cells. This indicates that the timed surge in D2-T3 signaling critically determines the fate of developing human hepatoblasts and the transcriptome of the maturing hepatocytes, with physiological and clinical implications for how the liver handles energy substrates.
2024-01-24 | GSE245250 | GEO
Project description:Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here, we studied human induced pluripotent stem cell-derived (iPSC-derived) hepatic organoids and identified a robust induction of DIO2 expression (the deiodinase that activates T4 to T3) that occurs in hepatoblasts. The surge in DIO2-T3 (the deiodinase that activates thyroxine [T4] to triiodothyronine [T3]) persists until the hepatoblasts differentiate into hepatocyte- or cholangiocyte-like cells, neither of which expresses DIO2. Preventing the induction of the DIO2-T3 signaling modified the expression of key transcription factors, decreased the number of hepatocyte-like cells by ~60%, and increased the number of cholangiocyte-like cells by ~55% without affecting the growth or the size of the mature liver organoid. Physiological levels of T3 could not fully restore the transition from hepatoblasts to mature cells. This indicates that the timed surge in DIO2-T3 signaling critically determines the fate of developing human hepatoblasts and the transcriptome of the maturing hepatocytes, with physiological and clinical implications for how the liver handles energy substrates.
| S-EPMC10795825 | biostudies-literature
Project description:To investigate the role of THRβ1 action in human iPSC-derived hepatocytes. We then performed gene expression profiling analysis using data obtained from RNA-seq of WT and THRBKO human iPSCs-derived hepatocytes in presence and absence of T3.
2024-11-01 | GSE270233 | GEO
Project description:Whole transcriptome analysis of iPSC derived hepatic organoids cultures
| PRJNA576358 | ENA
Project description:Hepatocytes generated from human induced pluripotent stem cells (hiPSCs) are unprecedented resources for pharmaceuticals and cell therapy. However, little attention has so far been paid to variations among hiPSC lines in terms of their hepatic differentiation. We developed an improved hepatic differentiation protocol and compared multiple hiPSC lines. This comparison indicated that the hepatic differentiation propensity varies among sibling hiPSC clones derived from the same adult human dermal fibroblasts (aHDFs). In addition, hiPSC clones derived from peripheral blood cells (PB-iPSCs) consistently showed good hepatic differentiation efficiency, whereas many hiPSC clones from adult dermal fibroblasts (aHDF-iPSCs) showed poor hepatic differentiation. However, when we compared hiPSCs from blood and dermal fibroblasts from the same individuals, we found that variations in hepatic differentiation were largely attributable to donor differences, rather than to the types of the original cells. In order to understand the molecular mechanisms underlying the observed variations in hepatic differentiation, we performed microarray analyses of sibling aHDF-iPSC clones, and aHDF- and PB-iPSC clones from the same individuals. sibling aHDF-iPSC clones (201B6 and 201B7; derived from the same aHDFs) (1) undifferentiated state (n=4, biological replicate #1-#4) (2) CXCR4-positive cell populations sorted by flowcytometry after 7 days of endodermal differentiation (n=4, biological replicate #1-#4) (3) CXCR4-negative cell populations sorted by flowcytometry after 7 days of endodermal differentiation (n=4, biological replicate #1-#4)
2012-07-15 | E-GEOD-38152 | biostudies-arrayexpress
Project description:Thyroid hormone (TH) influences metabolic pathways by binding to specific receptors (TRs), which are conditional transcription factors. T3 works through TRs to induce fibroblast growth factor (FGF) 21, a peptide hormone that is usually induced in fasting and influences lipid and carbohydrate metabolism via local hepatic and systemic endocrine effects. While administered TH and FGF21 display overlapping actions, including reductions in serum lipids, current models suggest that these hormones act independently in vivo. Here, we examined mechanisms of TH regulation of FGF21 expression and tested the possibility that FGF21 is required for induction of hepatic TH-responsive genes. We confirm that active TH (T3) and the TRβ selective thyromimetic GC-1 increase FGF21 transcript and peptide levels in mouse liver and that this effect requires TRβ. T3 also induces FGF21 in cultured hepatocytes and this effect involves direct actions of TRβ1, which binds a TRE within intron 2 of FGF21. Gene expression profiles in wild type and FGF21 knockout mice are highly similar indicating that FGF21 is dispensable for the majority of hepatic T3 gene responses. A small subset of genes displays diminished T3 response in the absence of FGF21. However, most of these are not obviously involved in T3-dependent hepatic lipid and carbohydrate metabolic processes. Accordingly, T3-dependent effects upon serum lipids are maintained in the FGF21-/- background. Our findings suggest that T3 regulates genes involved in classical hepatic metabolic responses independently of FGF21.
2014-12-31 | GSE58062 | GEO
Project description:Hepatocytes generated from human induced pluripotent stem cells (hiPSCs) are unprecedented resources for pharmaceuticals and cell therapy. However, little attention has so far been paid to variations among hiPSC lines in terms of their hepatic differentiation. We developed an improved hepatic differentiation protocol and compared multiple hiPSC lines. This comparison indicated that the hepatic differentiation propensity varies among sibling hiPSC clones derived from the same adult human dermal fibroblasts (aHDFs). In addition, hiPSC clones derived from peripheral blood cells (PB-iPSCs) consistently showed good hepatic differentiation efficiency, whereas many hiPSC clones from adult dermal fibroblasts (aHDF-iPSCs) showed poor hepatic differentiation. However, when we compared hiPSCs from blood and dermal fibroblasts from the same individuals, we found that variations in hepatic differentiation were largely attributable to donor differences, rather than to the types of the original cells. In order to understand the molecular mechanisms underlying the observed variations in hepatic differentiation, we performed microarray analyses of sibling aHDF-iPSC clones, and aHDF- and PB-iPSC clones from the same individuals.
2012-07-16 | GSE38152 | GEO
Project description:Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes
| PRJNA1125486 | ENA
Project description:Our goal was to demonstrate the similarity between the original keratinocytes and iPSC-derived keratinocytes from the same individual Profiles of original keratinocytes, iPSCs, IPSC-derived keratinocytes, iPSC-derived fibroblasts from a single individual and normal fibroblasts from a second individual were compared
2014-12-01 | GSE60991 | GEO
Project description:Bacillus sp. T3 strain:T3 Genome sequencing
| PRJNA1012702 | ENA