Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells
| Autor: | Somdutta Mukherjee, Paul Gadue, Deborah L. French |
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| Rok vydání: | 2021 |
| Předmět: |
Pluripotent Stem Cells
Blotting Western Induced Pluripotent Stem Cells Biology liver Biochemistry Cell Line Mice Species Specificity Downregulation and upregulation Report Gene expression Genetics medicine Animals Humans pancreas RNA-Seq Progenitor cell Induced pluripotent stem cell development Hepatocyte differentiation Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Cell Differentiation Cell Biology TBX3 Chromatin Cell biology medicine.anatomical_structure Mutation Hepatocytes PDX1 T-Box Domain Proteins Pancreas Developmental Biology |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| Popis: | Summary Tbx3 has been identified as a regulator of liver development in the mouse, but its function in human liver development remains unknown. TBX3 mutant human pluripotent stem cell (PSC) lines were generated using CRISPR/Cas9 genome editing. TBX3 loss led to impaired liver differentiation and an upregulation of pancreatic gene expression, including PDX1, during a hepatocyte differentiation protocol. Other pancreatic genes, including NEUROG3 and NKX2.2, displayed more open chromatin in the TBX3 mutant hepatoblasts. Using a pancreatic differentiation protocol, cells lacking TBX3 generated more pancreatic progenitors and had an enhanced pancreatic gene expression signature at the expense of hepatic gene expression. These data highlight a potential role of TBX3 in regulating hepatic and pancreatic domains during foregut patterning, with implications for enhancing the generation of pancreatic progenitors from PSCs. Graphical abstract Highlights • TBX3 null PSCs have impaired hepatocyte differentiation capacity • TBX3 null hepatocytes have aberrant expression of pancreatic genes, including PDX1 • TBX3 null PSCs have enhanced differentiation capacity into pancreatic progenitors • Loss of TBX3 leads to increased chromatin accessibility of many pancreatic genes Mukherjee et al. describe a potential role of TBX3 in patterning hepatic versus pancreatic domains during foregut development. Differentiation of TBX3 null PSCs using a hepatocyte differentiation protocol display impaired hepatocyte gene expression and upregulated expression and chromatin accessibility of pancreatic genes such as PDX1. Using a pancreatic differentiation protocol, TBX3 null PSCs have increased efficiency in pancreatic progenitor generation. |
| Databáze: | OpenAIRE |
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