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FGF2 Inhibits Early Pancreatic Lineage Specification during Differentiation of Human Embryonic Stem Cells
Rabea Dettmer1, Karsten Cirksena1, Julia Münchhoff1
1Institute of Clinical Biochemistry, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany.
Abstract:
Growth factors are important regulators during organ development. For many vertebrates (but not humans) it is known how they contribute to the formation and expansion of PDX1-positive cells during pancreas organogenesis. Here, the effects of the fibroblast growth factors FGF2, FGF7, FGF10, and epidermal growth factor (EGF) on pancreas development in humans were assessed by using human pluripotent stem cells (hPSCs). During this, FGF2 was identified as a potent anti-pancreatic factor whereas FGF7, FGF10, and EGF increased the cell mass while retaining PDX1-positivity. FGF2 increased the expression of the anti-pancreatic factor sonic hedgehog (SHH) while suppressing PDX1 in a dose-dependent manner. Differentiating cells secreted SHH to the medium and we interrogated the cells' secretome during differentiation to globally examine the composition of secreted signaling factors. Members of the TGF-beta-, Wnt-, and FGF-pathways were detected. FGF17 showed a suppressive anti-pancreatic effect comparable to FGF2. By inhibition of specific branches of FGF-receptor signaling, we allocated the SHH-induction by FGF2 to MEK/ERK-signaling and the anti-pancreatic effect of FGF2 to the receptor variant FGFR1c or 3c. Altogether, we report findings on the paracrine activity of differentiating hPSCs during generation of pancreatic progenitors. These observations suggest a different role for FGF2 in humans compared to animal models of pancreas organogenesis.
Insights
Fibroblast growth factor 2 (FGF2) inhibits human pancreas development by increasing sonic hedgehog (SHH) and suppressing PDX1. Other FGFs and EGF promote pancreatic progenitor expansion, revealing species-specific roles in organogenesis.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Endocrinology
Background:
- Growth factors orchestrate organ development, but their roles in human pancreas organogenesis differ from vertebrates.
- Understanding these factors is crucial for regenerative medicine and treating pancreatic diseases.
Purpose of the Study:
- To investigate the effects of fibroblast growth factors (FGFs) and epidermal growth factor (EGF) on human pancreas development using human pluripotent stem cells (hPSCs).
- To elucidate the signaling pathways involved in growth factor-mediated pancreatic progenitor formation.
Main Methods:
- Utilized hPSCs to model human pancreas organogenesis.
- Assessed the impact of FGF2, FGF7, FGF10, and EGF on PDX1-positive cell expansion and differentiation.
- Analyzed cell secretomes and employed receptor signaling inhibition to identify pathway involvement (MEK/ERK, FGFR1c/3c).
Main Results:
- FGF2 demonstrated potent anti-pancreatic effects, suppressing PDX1 and upregulating SHH in a dose-dependent manner.
- FGF7, FGF10, and EGF promoted cell mass expansion while maintaining PDX1 expression.
- FGF17 also exhibited anti-pancreatic activity; FGF2's effects were linked to MEK/ERK and FGFR1c/3c signaling.
Conclusions:
- FGF2 plays an inhibitory role in human pancreas development, contrasting its known functions in animal models.
- Specific FGFs and EGF are key regulators of human pancreatic progenitor expansion.
- These findings highlight species-specific mechanisms in pancreas organogenesis and offer insights for therapeutic strategies.
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