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Hedgehog signals in pancreatic differentiation from embryonic stem cells: revisiting the neglected
1Cell Differentiation Unit, Diabetes Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Abstract:
Recent demonstrations of insulin expression by progenies of mouse and human embryonic stem (ES) cells have attracted interest in setting up these cells as alternative sources of beta-cells needed in diabetes cell therapy. It is widely acknowledged that information gathered in the field of developmental biology as applied to the pancreas is of relevance for designing in vitro differentiation strategies. However, looking back at the protocols used so far, it appears that the natural route toward the pancreas, which goes via the definitive endoderm, was usually bypassed. As a consequence Hedgehog signaling, the earliest inhibitor of pancreas initiation from the endoderm, was generally not considered. A recall of the status of this pathway during ES cell differentiation appears necessary, especially in the light of findings that Activin A treatment of mouse and human ES cells coax them into definitive endoderm, a lineage showing wide Hedgehog ligands expression with the potential to hinder pancreatic programming.
Insights
Embryonic stem cells (ESCs) can become insulin-producing beta-cells for diabetes therapy. However, bypassing the definitive endoderm stage during differentiation may hinder pancreatic programming due to unconsidered Hedgehog signaling.
Area of Science:
- Stem cell biology
- Developmental biology
- Endocrinology
Background:
- Embryonic stem cells (ESCs) show promise for generating insulin-producing beta-cells for diabetes cell therapy.
- Pancreatic developmental biology informs in vitro differentiation strategies.
- Current protocols often bypass the definitive endoderm stage, a crucial step in pancreatic development.
Purpose of the Study:
- To highlight the importance of considering Hedgehog signaling during ESC differentiation into pancreatic beta-cells.
- To emphasize the role of definitive endoderm in pancreatic programming.
- To address potential hindrances in beta-cell generation from ESCs.
Main Methods:
- Review of existing ESC differentiation protocols.
- Analysis of developmental biology findings related to pancreas formation.
- Consideration of Activin A's role in inducing definitive endoderm in ESCs.
Main Results:
- Protocols often circumvent the natural developmental pathway via definitive endoderm.
- Hedgehog signaling, an early inhibitor of pancreas development, is frequently overlooked.
- Activin A induces definitive endoderm, which expresses Hedgehog ligands that may impede pancreatic programming.
Conclusions:
- Revisiting Hedgehog pathway status during ESC differentiation is crucial.
- Understanding definitive endoderm's role is key for effective beta-cell generation.
- Future strategies must integrate developmental cues to optimize ESC-based diabetes therapy.
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