Fibroblast Growth factor signaling in lipofibroblast formation and transdifferentiation during normal lung development and fibrosis
Final Report Abstract
Our research proposal was divided into three CreERT2 parts: a first part focussing on the generation and characterization of the Fgf10-CreERT2 knock in line required for this study, a second part focussing on the differentiation of the mesenchymal cells with a particular emphasis on the lipofibroblasts and a third part examining the importance of the lipofibroblasts and FGF signaling in fibrosis. As key findings for the first part, we showed that Intron1 of the Fgf10 gene is full of regulatory elements controlling Fgf10 expression. We concluded that next generation of knock in animal models to report Fgf10 expression and/or label Fgf10-positive cells in vivo should target the 3' untranslated region of Fgf10 thereby allowing to conserve normal Fgf10 expression and efficient and faithful Fgf10 reporter expression. We also reported that lipofibroblasts arise from Fgf10-positive cells suggesting that Fgf10, made by the Lipofibroblasts could be critical in maintaining the differentiation or the survival of the Alveolar epithelial type II cells, a critical cell type which is closely connected to the lipofibroblasts. As key findings for the second part, we show that Fgf10 acts directly on the mesenchyme to allow the differentiation of the LIF. Fgf10 acts via Fgfr1b and Fgfr2b. We propose that recombinant FGF10 could be used to trigger the differentiation of the mesenchyme towards the LIF phenotype. We also reported that the deletion of TGFb receptor ALK5 in the lung mesenchyme leads to more LIFs and less aSMA-positive fibroblasts. We propose that TGFb can be used to inhibit LIF formation during development. LIF and aSMA-positive fibroblasts could have a common progenitor which can be pushed towards tle LIF or the MYF phenotype. This could have serious implications in lung fibrosis. We also demonstrated that activation of Wnt signaling in the mesenchyme (via Pten deletion) leads to defects in angioblast differentiation into endothelial cells as well as accumulation of the angioblast cell population associated with disorganized capillary beds. These results suggest that inhibition of the mesenchymal Wnt signaling in fetuses at risk of developping alveolar capillary dysplasia may allow to attenuate some of the vascular defects. One limitation is that Wnt inhibitors are not specific to the mesenchyme. They will also act on the epithelium. As key findings for the third part, we found that Lipofibroblasts give rise to 'activated myofibroblasts" during fibrosis formation and vice-versa during fibrosis resolution. Rosiglitazone antagonizes the effect of TGFb and pushed the fibroblasts towards the lipofibroblast phenotype. We propose that PPARg agonist or FGF10 can be used to enhance fibrosis resolution in patients with Idiopathic pulmonary fibrosis. We also showed increased FGF1-FGFR signaling in IPF patients. This increase may contribute to the pathogenesis of lung fibrosis by supporting fibroblast migration and increased MAPK-signaling. Therefore, FGF1 signaling inhibitors may be able to attenuate lung fibrosis in patients with IPF. Surprising were the similarities between adipogenesis/lipogenesis and the formation of the LIF during lung development. The paper of El Agha et al. (2017, Cell Stem Cell) was recognized in 2017 by the Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin as the the best work in fundamental science 2017 (https://www.pneumologie.de/wissenschaft-forschung/ausschreibungenpreise/forschungspreise/).
Publications
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(2012) Characterization of a novel Fibroblast growth factor 10 (Fgf10) knock-in mouse line to target mesenchymal progenitors during embryonic development. PLoS One. 7(6):e38452
El Agha, E., Al Alam, D., Carraro, G., MacKenzie, B., Goth, K., Langhe, S.P., Voswinckel, R., Hajihosseini, M.K., Rehan, V.K. and Bellusci, S.
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(2012) Mesodermal Deletion of Pten leads to Alveolar Capillary Dysplasia-like phenotype. Journal of Clinical Investigation
Tiozzo, C., Carraro, G., Al Alam, D., Baptista, S., Danopoulos, S., Li, A., Lavarreda-Pearce, M., Li, C., De Langhe, S., Chan, B., Borok, Z., Bellusci, S., and Minoo, P.
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(2014) Fgf10-positive cells represent a multipotent progenitor cell population during lung development and postnatally. Development 141(2):296-306
El Agha, E., Herold, S. Al Alam, D., Quantius, J., MacKenzie, B., Carraro, C., Minoo, P., Seeger, W., and Bellusci, S.
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(2015) Characterization of the platelet-derived growth factor receptor α-positive cell lineage during murine late lung development. Am J Physiol Lung Cell Mol Physiol., 2015 Aug 28
Ntokou A, Klein F, Dontireddy D, Becker S, Bellusci S, Richardson WD, Szibor M, Braun T, Morty RE, Seeger W, Voswinckel R, Ahlbrecht K
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(2015) Evidence for the involvement of Fibroblast Growth Factor 10 in lipofibroblast formation during embryonic lung development. Development, 142(23):4139-50
Al Alam D., El Agha, E., Sakurai, R., Kheirollahi, V., Moiseenko, A., Danopoulos, S., Shrestha, S., Schmoldt, C., Quantius, J., Herold, S., Chao, C-M., Tiozzo, C., De Langhe, S., Plikus, M.V., Thornton, M., Grubbs, B., Minoo, P., Rehan, V.K. and Bellusci, S.
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(2015) Increased FGF1-FGFR expression in Idiopathic Pulmonary Fibrosis. Respiratory Research, 16: 83
MacKenzie, B., Henneke, I., Korfei, M., Hezel, S., Wilhelm, J., El Agha, E., Klapetko, W., Seeger, S., Günther, A. and Bellusci, S.
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(2016) Mesodermal Alk5 Controls Lung Myofibroblast versus Lipofibroblast Cell Fate. BMC Biology, 16(14):19
Li, A., Ma, S., Smith, S.M., Lee, M.K., Fischer, A., Borok, Z., Bellusci, S., Changgong Li, C., Parviz Minoo, P.
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(2017) Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis. Cell Stem Cell, 20(2):261-273
El Agha, E., Moiseenko, A., Kheirollahi, V., De Langhe, S., Cmkovic, S., Kosanovic, D., Kwapiszewska, G., Szibor, M., Kosanovic,, D., Schwind, F., Schermuly, R.T., Henneke, I., MacKenzie, B., Quantius, J., Herold, S., Ahlbrecht, K., Braun, T., Morty, R.E., Gunther, A., Seeger, W. and Bellusci, S.
