The nuclear receptor THRB facilitates differentiation of human PSCs into more mature hepatocytes

Ma, Haiting; Zwaan, Esmée de; Guo, Yang; Cejas, Paloma; Thiru, Prathapan; Bunt, Martijn van de; Jeppesen, Jacob; Syamala, Sudeepa; Dall’Agnese, Alessandra; Abraham, Brian J.; Fu, Dongdong; Garrett-Engele, Carrie M.; Lee, Tong Ihn; Long, Henry W.; Griffith, Linda G.; Young, Richard A.; Jaenisch, Rudolf

doi:10.1016/j.stem.2022.03.015

Cited by 10 publications

(7 citation statements)

References 85 publications

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“…Computationally, we identified the inhibition of TGFB signalling and T3 as factors to enhance HLC maturity in vitro. Our findings that T3 can be used to promote hepatic maturation are consistent with other recent reports [39,40]. Thyroid hormone was previously shown to both directly [41] and indirectly [42] upregulate CEBPA signalling and increases hepatic CEBPA and CEBPB levels in hypothyroid rats [43].…”

Section: Discussionsupporting

confidence: 93%

Thyroid hormone and ALK5 inhibitor improve maturation of human pluripotent stem cell derived hepatocytes

Withey

Gerrard

Leeson

et al. 2022

Preprint

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Hepatocytes derived from human pluripotent stem cells (PSCs) hold great promise for modeling human liver disease, in vitro hepatotoxicity testing, and future cellular therapy. However, current protocols generate hepatocyte-like cells (HLCs) that resemble fetal hepatocytes, and thus do not accurately recapitulate the molecular identity and functions of the adult liver. To address this, we compared the transcriptomes of human fetal and adult liver to PSC-derived HLCs during progressive stages of in vitro differentiation. This revealed that during the final stages of in vitro differentiation the hepatic transcription factors HNF4A and CEBPA were sub-optimally expressed. Computational analyses predicted that ALK5i II (TGF-β receptor inhibitor) and thyroid hormone (T3) would be able to rectify this and improve HLC maturation. We next show that application of these molecules during hepatocyte differentiation indeed increases CEBPA and HNF4A mRNA and protein expression, and that these HLCs show enhanced albumin secretion, a 25-fold increase in CYP3A4 activity, and 10 to 100-fold increased expression of mature hepatic markers. We demonstrate that this improved maturation is effective across different cell lines and HLC differentiation protocols, and exemplifies that our approach provides a tractable template for identifying and targeting additional factors that that will fully mature human liver cells from human pluripotent stem cells.

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Section: Discussionsupporting

confidence: 93%

Thyroid hormone and ALK5 inhibitor improve maturation of human pluripotent stem cell derived hepatocytes

Withey

Gerrard

Leeson

et al. 2022

Preprint

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“…CEBPD has been demonstrated to promote growth, metastasis, and drug resistance in multiple tumor types and can serve as a potential target for cancer treatment 20 . Other significantly enriched TFs, such as NR1H4, THRB, and JUN, were reported to participate in the development process and maintain normal physiological functions in the liver 21–23 …”

Section: Resultsmentioning

confidence: 99%

“… 20 Other significantly enriched TFs, such as NR1H4, THRB, and JUN, were reported to participate in the development process and maintain normal physiological functions in the liver. 21 , 22 , 23 …”

Section: Resultsmentioning

confidence: 99%

Single‐cell characteristics and malignancy regulation of alpha‐fetoprotein‐producing gastric cancer

Mei

Wen

et al. 2023

Cancer Medicine

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Alpha-fetoprotein-producing gastric cancer (AFPGC) is a rare but highly malignant subtype of gastric cancer (GC) characterized by elevated serum alpha-fetoprotein (AFP) levels (>20 ng/mL). AFPGC accounts for 1.3%-15% of all GCs. 1 Patients with AFPGC have an aggressive clinical course, early occurrence of multiple organ metastases, primary multidrug resistance, and a poor prognosis. The 5-year survival rate of patients with stage IV AFPGC is 4.4%. 2 The pathogenesis of AFPGC is still not fully understood and effective therapeutic targets are lacking.In recent years, whole-exome sequencing (WES) has been used to study the genetic mutation profiles of AFPGC. In our previous study, we performed whole-exome sequencing of 29 cases of AFP-producing gastrointestinal cancer (AFPGI),

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“…64 Significant progress has been achieved in identifying molecular pathways necessary for fetal hepatocyte maturity, and subsequent optimized culture conditions have enabled considerable progresses in PSC-derived HLCs. 65 Hence, culture conditions for liver organoid models can similarly be optimized in the future to enhance the functional maturity of cells. • Wolman disease…”

Section: Hereditary Liver Diseasementioning

confidence: 99%

A decade of liver organoids: Advances in disease modeling

Liu¹,

Sheng²,

Ding³

et al. 2023

Clin Mol Hepatol

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Liver organoids are 3D cellular models of tissue in which cells interact to form unique structures in culture. Since their inception, liver organoids with various cellular compositions, structural features, and functional properties have been described over the past ten years. Methods to create these advanced human cell models range from simple tissue culture techniques to complex bioengineering approaches. These liver organoid culture platforms have been utilized in various liver research fields, including the modeling of liver diseases to regenerative therapy. This review will discuss how liver organoids are used to model diseases, including hereditary liver diseases, primary liver cancer, viral hepatitis, and nonalcoholic fatty liver disease. Specifically, we will focus on studies that utilized two widely adopted approaches: differentiation from pluripotent stem cells and epithelial organoids cultured from patient tissues. These approaches have enabled the generation of advanced human liver models and, more importantly, the establishment of patient-tailored models for evaluating individual-specific disease phenotypes and therapeutic responses.

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The nuclear receptor THRB facilitates differentiation of human PSCs into more mature hepatocytes

Cited by 10 publications

References 85 publications

Thyroid hormone and ALK5 inhibitor improve maturation of human pluripotent stem cell derived hepatocytes

Thyroid hormone and ALK5 inhibitor improve maturation of human pluripotent stem cell derived hepatocytes

Single‐cell characteristics and malignancy regulation of alpha‐fetoprotein‐producing gastric cancer

A decade of liver organoids: Advances in disease modeling

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