Increased thermal stability of FGF10 leads to ectopic signaling during development

Fibroblast growth factors (FGFs) control organ morphogenesis during development as well as tissue homeostasis and repair in the adult organism. Despite their importance, many mechanisms that regulate FGF function are still poorly understood. Interestingly, the thermodynamic stability of 22 mammalian FGFs varies widely, with some FGFs remaining stable at body temperature for more than 24 h, while others lose their activity within minutes. How thermodynamic stability contributes to the function of FGFs during development remains unknown. Here we show that FGF10, an important limb and lung morphogen, exists as an intrinsically unstable protein that is prone to unfolding and is rapidly inactivated at 37 °C. Using rationally driven directed mutagenesis, we have developed several highly stable (STAB) FGF10 variants with a melting temperature of over 19 °C more than that of wildtype FGF10. In cellular assays in vitro, the FGF10-STABs did not differ from wildtype FGF10 in terms of binding to FGF receptors, activation of downstream FGF receptor signaling in cells, and induction of gene expression. In mouse embryonal lung explants, FGF10-STABs, but not wildtype FGF10, suppressed branching, resulting in increased alveolarization and expansion of epithelial tissue. Similarly, FGF10-STAB1, but not FGF10 wildtype, inhibited the growth of mouse embryonic tibias and markedly altered limb morphogenesis when implanted into chicken limb buds, collectively demonstrating that thermal instability should be considered an important regulator of FGF function that prevents ectopic signaling. Furthermore, we show enhanced differentiation of human iPSC-derived lung organoids and improved regeneration in ex vivo lung injury models mediated by FGF10-STABs, suggesting an application in cell therapy.

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Publication Details

Journal
Cellular and Molecular Life Sciences
Published
2025-04-21
DOI
https://doi.org/10.1007/s00018-025-05681-1
Citations
2
Primary Topic
Fibroblast Growth Factor Research
Type
article
Field-Weighted Citation Impact
1.61

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article

Increased thermal stability of FGF10 leads to ectopic signaling during development

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2 citations
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Fibroblast Growth Factor Research
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article

Increased thermal stability of FGF10 leads to ectopic signaling during development

Kalina Hristova, Michaela Kunova Bosakova, David Bednář, Jennifer Zieba, Deborah Krakow, Bohumil Fafílek, Magdalena Wujak, Gustavo Rico-Llanos, Jan Frič, Pavel Krejčı́, Jan Kubovčiak, Katerina Svozilova, Rafał Bartoszewski, Małgorzata Zakrzewska, Karolina Baran, Veronika Štěpánková, Stefan Hadžić, Kelly Karl, Julia Chudzian, Edma Loku, Michael Killinger, Daniel Krowarsch, Petr Kašpárek, Veronika Bosáková, Eva Hrubá, Marcela Buchtová, Marie Delattre, Aneta Horáčková, Aleksandra Czyrek, Radka Chaloupková, Tereza Szotkowská, Jan Procházka, Radislav Sedlacek, Michaela Stroblova, Veronika Laskova
article en
2 citations

Abstract

Fibroblast growth factors (FGFs) control organ morphogenesis during development as well as tissue homeostasis and repair in the adult organism. Despite their importance, many mechanisms that regulate FGF function are still poorly understood. Interestingly, the thermodynamic stability of 22 mammalian FGFs varies widely, with some FGFs remaining stable at body temperature for more than 24 h, while others lose their activity within minutes. How thermodynamic stability contributes to the function of FGFs during development remains unknown. Here we show that FGF10, an important limb and lung morphogen, exists as an intrinsically unstable protein that is prone to unfolding and is rapidly inactivated at 37 °C. Using rationally driven directed mutagenesis, we have developed several highly stable (STAB) FGF10 variants with a melting temperature of over 19 °C more than that of wildtype FGF10. In cellular assays in vitro, the FGF10-STABs did not differ from wildtype FGF10 in terms of binding to FGF receptors, activation of downstream FGF receptor signaling in cells, and induction of gene expression. In mouse embryonal lung explants, FGF10-STABs, but not wildtype FGF10, suppressed branching, resulting in increased alveolarization and expansion of epithelial tissue. Similarly, FGF10-STAB1, but not FGF10 wildtype, inhibited the growth of mouse embryonic tibias and markedly altered limb morphogenesis when implanted into chicken limb buds, collectively demonstrating that thermal instability should be considered an important regulator of FGF function that prevents ectopic signaling. Furthermore, we show enhanced differentiation of human iPSC-derived lung organoids and improved regeneration in ex vivo lung injury models mediated by FGF10-STABs, suggesting an application in cell therapy.

Cellular and Molecular Life SciencesVol. 82(1)
Wrocław University of Science and Technology (PL), Johns Hopkins University (US), University of California, Los Angeles (US), Masaryk University (CZ), University of Wrocław (PL), Nicolaus Copernicus University (PL), Institute of Haematology and Blood Transfusion (CZ), Czech Academy of Sciences, Institute of Animal Physiology and Genetics (CZ), University Hospital Brno (CZ), International Clinical Research Center, St. Anne's University Hospital Brno (CZ), Enantis (Czechia) (CZ), St. Anne's University Hospital Brno (CZ), Czech Academy of Sciences, Institute of Molecular Genetics (CZ), Cardio-Pulmonary Institute (DE)
European Commission, Grantová Agentura České Republiky, Akademie Věd České Republiky, Masarykova Univerzita, Lékařská fakulta, Masarykova univerzita, Horizon 2020 Framework Programme
Openalex Percentile: Top 18%
Fibroblast Growth Factor Research
1.61
DOIOpen Access PDFOpenAlex
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