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Updated: Nov 20, 2025
Differentiation of Human Pluripotent Stem Cells Into Pancreatic Beta-Cell Precursors in a 2D Culture System
Published on: December 16, 2021
Aberrant development of pancreatic beta cells derived from human iPSCs with FOXA2 deficiency
Ahmed K Elsayed1, Ihab Younis2, Gowher Ali1
1Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
Abstract:
FOXA2 has been identified as an essential factor for pancreas development and emerging evidence supports an association between FOXA2 and diabetes. Although the role of FOXA2 during pancreatic development is well-studied in animal models, its role during human islet cell development remains unclear. Here, we generated induced pluripotent stem cells (iPSCs) from a patient with FOXA2 haploinsufficiency (FOXA2+/- iPSCs) followed by beta-cell differentiation to understand the role of FOXA2 during pancreatic beta-cell development. Our results showed that FOXA2 haploinsufficiency resulted in aberrant expression of genes essential for the differentiation and proper functioning of beta cells. At pancreatic progenitor (PP2) and endocrine progenitor (EPs) stages, transcriptome analysis showed downregulation in genes associated with pancreatic development and diabetes and upregulation in genes associated with nervous system development and WNT signaling pathway. Knockout of FOXA2 in control iPSCs (FOXA2-/- iPSCs) led to severe phenotypes in EPs and beta-cell stages. The expression of NGN3 and its downstream targets at EPs as well as INSUILIN and GLUCAGON at the beta-cell stage, were almost absent in the cells derived from FOXA2-/- iPSCs. These findings indicate that FOXA2 is crucial for human pancreatic endocrine development and its defect may lead to diabetes based on FOXA2 dosage.
Insights
Forkhead box A2 (FOXA2) is vital for human pancreatic development and its deficiency is linked to diabetes. Haploinsufficiency impairs beta-cell differentiation, highlighting FOXA2
Area of Science:
- Endocrinology
- Developmental Biology
- Stem Cell Biology
Background:
- FOXA2 is crucial for pancreas development in animal models.
- Its role in human islet cell development is not well understood.
- Emerging evidence links FOXA2 to diabetes pathogenesis.
Purpose of the Study:
- To investigate the role of FOXA2 in human pancreatic beta-cell development.
- To understand the impact of FOXA2 haploinsufficiency on beta-cell differentiation.
- To elucidate the function of FOXA2 dosage in human pancreatic endocrine development.
Main Methods:
- Generated FOXA2 haploinsufficient (FOXA2+/–) and knockout (FOXA2–/–) human induced pluripotent stem cells (iPSCs).
- Differentiated iPSCs towards beta-cell lineage.
- Performed transcriptome analysis at pancreatic progenitor (PP2) and endocrine progenitor (EPs) stages.
Main Results:
- FOXA2 haploinsufficiency led to aberrant gene expression essential for beta-cell differentiation and function.
- Transcriptome analysis revealed downregulation of pancreatic development genes and upregulation of nervous system and WNT signaling genes.
- FOXA2 knockout severely impaired endocrine progenitor development and expression of key beta-cell markers (NGN3, INSULIN, GLUCAGON).
Conclusions:
- FOXA2 is essential for human pancreatic endocrine development.
- FOXA2 dosage is critical, and its deficiency can lead to impaired beta-cell development, potentially contributing to diabetes.
- These findings provide insights into FOXA2's role in beta-cell biology and diabetes.
