Cyp26b1 is required for proper airway epithelial differentiation during lung development
Posted on: 19 August 2019 , updated on: 21 February 2020
Preprint posted on 20 June 2019
Article now published in Development at https://dev.biologists.org/content/147/4/dev181560
Endothelial cells fine-tune retinoic acid levels through Cyp261b, enabling the differentiation of lung epithelial cells.
Selected by Julio Sainz de Aja
Categories: cell biology, developmental biology, molecular biology
Why I think this paper is important for the scientific community:
The effort to achieve differentiated human lungs in vitro out of human induced pluripotent stem cells (hiPSCs) is an ongoing struggle in the fields of stem cell biology and development. It is clear that to correctly and fully differentiate human lung cells, or indeed any organ, it is crucial to understand the developmental process by which those cells are produced.
Nowadays, most of the lung organoid differentiation methods rely on co-culturing stem cells with niche cells (Lee et al., 2017; Leeman et al., 2019). Differentiation from hiPSCs to lung organoids have been achieved in the last years (McCauley et al., 2017), however, cells remain in their progenitor state, being unable to differentiate towards the final differentiation stage of lung development. In order to understand how the in vitro cultures could be improved, it is important to study the interaction in vivo between stromal, endothelial or smooth muscle cells and the lung epithelial cells in the context of differentiation.
In this work, Daniel and colleagues explore the role of endothelial cells in lung differentiation. They observe that levels of Retinoic acid (RA) are crucial for proper lung distal differentiation and that Cyp26b1, a RA-catabolizing enzyme highly expressed in endothelial cells, is crucial for the late differentiation of the lung distal progenitor population. More specifically, AT2 cells (surfactant producing cells that in the alveoli can give rise to AT1 cells) fail to differentiate towards AT1 (alveoli epithelial cells in charge of the oxygen exchange). Since alveoli differentiation from hiPS cells is challenging using current protocols (Jacob et al., 2017), this work could point to a possible solution for this problem in the lung organoid field.
Background:
The spatiotemporal regulation of RA is vital for proper specification of the organs during embryonic development and further on (Rhinn and Dollé, 2012). In this regard, RA catabolizing enzymes play an important role in regulating the levels of RA and determining the spatial distribution of this molecule (Abu-Abed et al., 2002). More specifically, in the lung, it is known that enzymes that synthesize RA are necessary for lung bud growth (Ribes et al., 2006). However, the role of the RA-catabolizing Cyp26 enzymes remains unknown. Cyp26a1 is expressed in the lung epithelium in early stages, while Cyp26b1 is expressed in the mesenchyme in later stages of development (Abu-Abed et al., 2002). The question remains as to whether these enzymes have a role in lung distal differentiation, particularly Cyp26b1 given that it is expressed in later stages of lung development.
Key findings:
Cyp26b1 is highly expressed in endothelial cells of the developing lung. The authors generated two different KO for Cyp26b1 by CRISPR/Cas9, in both distal airway morphogenesis is delayed at E16.5 with the lung’s lumens being small and rarely open (Figure A). KO mice died right after birth probably due to respiratory distress, as they display air hunger reflexes. More specifically, AT2 cells fail to differentiate into AT1 cells. The authors quantify AT2 cells using Lamp3 and pro-SPC, and AT1 with Aqp5 and Pdpn by IF, western and qPCR (Figure B). Other cell types in the lung such as proximal airways, stroma, endothelia and lymphatics are not affected in the KO. Exogenous RA administered to the pregnant mothers has a similar phenotype as the Cyp26b1 KO, although AT2 cells only increased in the heterozygous embryos treated but not the wildtypes treated with exogenous RA (Figure C). Cyp26b1 full KO treated with exogenous RA died by E18.5. Still, exogenous RA and loss of Cyp26b1 have a different transcriptional response in a number of RA targets by qPCR, suggesting the Cyp26b1 phenotype is not completely RA-dependent.
Figure A: Loss of Cyp26b1 in lung endothelial cells delays the formation of distal airways.
Figure B: Cyp26b1 KO lungs have increased cellular density and reduced AT1 cells presence.
Figure C: Cyp26b1phenotype is at least partially due to the excess of RA.
Questions to the authors:
- Would you expect the same results in lung epithelial cells in a conditional KO for endothelial cells?
- How do you believe endothelial cells interact with epithelial cells in the RA context? Do they interact physically with each other?
- Have you contemplated following this work in adult lung, to see whether Cyp26b1 has an impact in alveoli regeneration upon injury? Is it still expressed in endothelial cells?
Bibliography
Abu-Abed, S., MacLean, G., Fraulob, V., Chambon, P., Petkovich, M., and Dollé, P. (2002). Differential expression of the retinoic acid-metabolizing enzymes CYP26A1 and CYP26B1 during murine organogenesis. Mech. Dev. 110, 173–177.
Jacob, A., Morley, M., Hawkins, F., McCauley, K.B., Jean, J.C., Heins, H., Na, C.-L., Weaver, T.E., Vedaie, M., Hurley, K., et al. (2017). Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell 21, 472-488.e10.
Lee, J.-H., Tammela, T., Hofree, M., Jacks, T., Regev, A., and Kim Correspondence, C.F. (2017). Anatomically and Functionally Distinct Lung Mesenchymal Populations Marked by Lgr5 and Lgr6. Cell 170.
Leeman, K.T., Pessina, P., Lee, J.-H., and Kim, C.F. (2019). Mesenchymal Stem Cells Increase Alveolar Differentiation in Lung Progenitor Organoid Cultures. Sci. Rep. 9, 6479.
McCauley, K.B., Hawkins, F., Serra, M., Thomas, D.C., Jacob, A., and Kotton, D.N. (2017). Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling. Cell Stem Cell 20, 844-857.e6.
Rhinn, M., and Dollé, P. (2012). Retinoic acid signalling during development. Development 139, 843–858.
Ribes, V., Wang, Z., Dollé, P., Niederreither, K., and Gossler, A. (2006). Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling. Development 133, 351–361.
doi: https://doi.org/10.1242/prelights.13467
Read preprint
(No Ratings Yet)Sign up to customise the site to your preferences and to receive alerts
Register hereAlso in the cell biology category:
The RNA binding protein HNRNPA2B1 regulates RNA abundance and motor protein activity in neurites
Felipe Del Valle Batalla
Pharyngeal neuronal mechanisms governing sour taste perception in Drosophila melanogaster
Matthew Davies
Feedback regulation by the RhoA-specific GEF ARHGEF17 regulates actomyosin network disassembly
Vibha SINGH
Also in the developmental biology category:
Specialized signaling centers direct cell fate and spatial organization in a limb organoid model
Ryan Harrison
Adult caudal fin shape is imprinted in the embryonic fin fold
Isabella Cisneros
TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development
Reinier Prosee
Also in the molecular biology category:
The RNA binding protein HNRNPA2B1 regulates RNA abundance and motor protein activity in neurites
Felipe Del Valle Batalla
The role of ER exit sites in maintaining P-body organization and transmitting ER stress response during Drosophila melanogaster oogenesis
Jonathan Townson
Adult caudal fin shape is imprinted in the embryonic fin fold
Isabella Cisneros
preLists in the cell biology category:
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
| List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
| List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
| List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
| List by | Ana Dorrego-Rivas |
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
| List by | Dey Lab, Samantha Seah |
1
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
| List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
| List by | Paul Gerald L. Sanchez and Stefano Vianello |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
| List by | Pablo Ranea Robles |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
| List by | Dey Lab |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
| List by | Joseph Jose Thottacherry |
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
| List by | Dey Lab, Amanda Haage |
Also in the developmental biology category:
BSDB/GenSoc Spring Meeting 2024
A list of preprints highlighted at the British Society for Developmental Biology and Genetics Society joint Spring meeting 2024 at Warwick, UK.
| List by | Joyce Yu, Katherine Brown |
GfE/ DSDB meeting 2024
This preList highlights the preprints discussed at the 2024 joint German and Dutch developmental biology societies meeting that took place in March 2024 in Osnabrück, Germany.
| List by | Joyce Yu |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
| List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
| List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
| List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
2nd Conference of the Visegrád Group Society for Developmental Biology
Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)
| List by | Nándor Lipták |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
EMBL Conference: From functional genomics to systems biology
Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020
| List by | Jesus Victorino |
Single Cell Biology 2020
A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.
| List by | Alex Eve |
Society for Developmental Biology 79th Annual Meeting
Preprints at SDB 2020
| List by | Irepan Salvador-Martinez, Martin Estermann |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
| List by | Ana Dorrego-Rivas |
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
| List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
| List by | Paul Gerald L. Sanchez and Stefano Vianello |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EDBC Alicante 2019
Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.
| List by | Sergio Menchero et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
SDB 78th Annual Meeting 2019
A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.
| List by | Alex Eve |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
Young Embryologist Network Conference 2019
Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London
| List by | Alex Eve |
Pattern formation during development
The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.
| List by | Alexa Sadier |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
| List by | Dey Lab |
Zebrafish immunology
A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.
| List by | Shikha Nayar |
Also in the molecular biology category:
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |