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An Optimized Hepatocyte-like Cells Differentiation Protocol Using Machine Learning Assisted Approach and Multi-omics Analysis [WGS]

ABSTRACT: The hepatocyte is a vital cell type responsible for numerous physiological processes in the body. We developed a machine learning-based AI algorithm to monitor morphological changes in hESCs during their differentiation into mature hepatocytes.Furthermore, we developed a modified strategy that safely and efficiently produces HLCs from hESCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246556 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Background: Thioredoxin-interacting protein (TXNIP) regulates endoplasmic reticulum (ER) and oxidative stress, impairing glucose homeostasis in diabetes. However, it is unclear if TXNIP deficiency can improve differentiation or functionality of human stem cell-derived somatic metabolic cells. Methods: Using CRISPR-Cas12a genome editing, we generated TXNIP-deficient (TXNIP-/-) H1 human embryonic stem cells (H1-hESCs). These cells were differentiated into hepatocyte-like cells (HLCs) and stem-cell-derived insulin-producing islets (SC-islets). TXNIP-/- and TXNIP+/+ SC-islet maturation and functionality was assessed by implantation under the kidney capsule of NOD-SCID mice. Results: TXNIP deficiency significantly increased H1-hESC proliferation without affecting pluripotency, viability, or differentiation potential into HLCs and SC-islets. Bulk RNA-sequencing of thapsigargin-treated TXNIP-/- and TXNIP+/+ hESCs revealed differential expression of stress-responsive genes, with enriched apoptosis-related pathways in TXNIP+/+ cells but minimal transcriptional changes specific to TXNIP deficiency. In HLCs, TXNIP deletion reduced albumin secretion and insulin signalling, as indicated by decreased AKT phosphorylation, while showing no differences in glycolytic activity or lipid metabolism markers. Under thapsigargin-induced ER stress, TXNIP-/- HLCs exhibited transiently reduced eIF2α phosphorylation and lower BiP expression, suggesting compromised adaptive responses to prolonged stress. SC-islets derived from TXNIP-/- hESCs showed comparable viability, endocrine cell composition, and cytokine responses to TXNIP+/+ islets. Upon IFNα and IFNγ treatment, STAT1 phosphorylation was increased in TXNIP-/- SC-islets, indicating that IFN signalling remains active despite TXNIP deficiency. TXNIP-/- or TXNIP+/+ islets SC-islets implanted into NOD-SCID mice produced human C-peptide and responded to glucose stimulation. However, TXNIP-/- SC-islets showed no enhancement in glycaemic control or glucose-stimulated insulin secretion compared to controls. Conclusions: Our study demonstrates that TXNIP deficiency does not improve the differentiation of HLCs and SC-islets. We report the generation and characterization of TXNIP-/- and TXNIP+/+ H1-hESCs, HLCs and SC-islets as robust models for future studies of TXNIP’s role in metabolic cell biology.

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An Optimized Hepatocyte-like Cells Differentiation Protocol Using Machine Learning Assisted Approach and Multi-omics Analysis [WGS]

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