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1. Author Correction: Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro

Author

Garcia-Alonso, Luz, Handfield, Louis-François, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., Vento-Tormo, Roser, Garcia-Alonso, Luz, Handfield, Louis-François, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., and Vento-Tormo, Roser

Published
2022
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2. A human embryonic limb cell atlas resolved in space and time

Author

Zhang, Bao, He, Peng, Lawrence, John E., Wang, Shuaiyu, Tuck, Elizabeth, Williams, Brian, Roberts, Kenny, Kleshchevnikov, Vitalii, Mamanova, Lira, Bolt, Liam, Polanski, Krzysztof, Elmentaite, Rasa, Fasouli, Eirini S., Prete, Martin, He, Xiaoling, Yayon, Nadav, Fu, Yixi, Yang, Hao, Liang, Chen, Zhang, Hui, FitzPatrick, David R., Firth, Helen, Dean, Andrew, Barker, Roger A., Storer, Mekayla A., Wold, Barbara J., Zhang, Hongbo, Teichmann, Sarah A., Zhang, Bao, He, Peng, Lawrence, John E., Wang, Shuaiyu, Tuck, Elizabeth, Williams, Brian, Roberts, Kenny, Kleshchevnikov, Vitalii, Mamanova, Lira, Bolt, Liam, Polanski, Krzysztof, Elmentaite, Rasa, Fasouli, Eirini S., Prete, Martin, He, Xiaoling, Yayon, Nadav, Fu, Yixi, Yang, Hao, Liang, Chen, Zhang, Hui, FitzPatrick, David R., Firth, Helen, Dean, Andrew, Barker, Roger A., Storer, Mekayla A., Wold, Barbara J., Zhang, Hongbo, and Teichmann, Sarah A.

Abstract

Human limbs emerge during the fourth post-conception week as mesenchymal buds which develop into fully-formed limbs over the subsequent months. Limb development is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common. Decades of work with model organisms has outlined the fundamental processes underlying vertebrate limb development, but an in-depth characterisation of this process in humans has yet to be performed. Here we detail the development of the human embryonic limb across space and time, using both single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells, progressing from a restricted number of multipotent progenitors to myriad mature cell states, and identify several novel cell populations, including perineural fibroblasts and multiple distinct mesenchymal states. We uncover two waves of human muscle development, each characterised by different cell states regulated by separate gene expression programmes. We identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity and validate this by performing MSC knock down in human embryonic myoblasts, which results in significant upregulation of late myogenic genes. Spatially mapping the cell types of the limb across a range of gestational ages demonstrates a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncovers two transcriptionally and spatially distinct populations of the progress zone, which we term “outer” and “transitional” layers. The latter exhibits a transcriptomic profile similar to that of the chondrocyte lineage, but lacking the key chondrogenic transcription factors SOX5,6 & 9. Finally, we perform scRNA-seq on murine embryonic limbs to facilitate cross-species developmental comparison at single-cell resolution, finding substantial homology between the two species.

Published
2022

3. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro

Author

Garcia-Alonso, Luz, Handfield, Louis-Francois, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-Eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., Vento-Tormo, Roser, Garcia-Alonso, Luz, Handfield, Louis-Francois, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-Eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., and Vento-Tormo, Roser

Abstract

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively.

Published
2021
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4. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro

Author

Garcia-Alonso, Luz, Handfield, Louis-Francois, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-Eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., Vento-Tormo, Roser, Garcia-Alonso, Luz, Handfield, Louis-Francois, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-Eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., and Vento-Tormo, Roser

Abstract

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively.

Published
2021
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5. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro

Author

Garcia-Alonso, Luz, Handfield, Louis-Francois, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-Eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., Vento-Tormo, Roser, Garcia-Alonso, Luz, Handfield, Louis-Francois, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-Eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., and Vento-Tormo, Roser

Abstract

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively.

Published
2021
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6. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro

Author

Garcia-Alonso, Luz, Handfield, Louis-François, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., Vento-Tormo, Roser, Garcia-Alonso, Luz, Handfield, Louis-François, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., and Vento-Tormo, Roser

Published
2021
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7. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro

Author

Garcia-Alonso, Luz, Handfield, Louis-Francois, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-Eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., Vento-Tormo, Roser, Garcia-Alonso, Luz, Handfield, Louis-Francois, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-Eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., and Vento-Tormo, Roser

Abstract

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively., Correction in: Nature Genetics, 55, page 165 (2023)DOI: 10.1038/s41588-022-01287-6

Published
2021
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8. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro

Author

Garcia-Alonso, Luz, Handfield, Louis-Francois, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-Eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., Vento-Tormo, Roser, Garcia-Alonso, Luz, Handfield, Louis-Francois, Roberts, Kenny, Nikolakopoulou, Konstantina, Fernando, Ridma C., Gardner, Lucy, Woodhams, Benjamin, Arutyunyan, Anna, Polanski, Krzysztof, Hoo, Regina, Sancho-Serra, Carmen, Li, Tong, Kwakwa, Kwasi, Tuck, Elizabeth, Lorenzi, Valentina, Massalha, Hassan, Prete, Martin, Kleshchevnikov, Vitalii, Tarkowska, Aleksandra, Porter, Tarryn, Mazzeo, Cecilia Icoresi, van Dongen, Stijn, Dabrowska, Monika, Vaskivskyi, Vasyl, Mahbubani, Krishnaa T., Park, Jong-Eun, Jimenez-Linan, Mercedes, Campos, Lia, Kiselev, Vladimir Yu., Lindskog, Cecilia, Ayuk, Paul, Prigmore, Elena, Stratton, Michael R., Saeb-Parsy, Kourosh, Moffett, Ashley, Moore, Luiza, Bayraktar, Omer A., Teichmann, Sarah A., Turco, Margherita Y., and Vento-Tormo, Roser

Abstract

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively., Correction in: Nature Genetics, 55, page 165 (2023)DOI: 10.1038/s41588-022-01287-6

Published
2021
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9. Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm

Author

Chetaille, Philippe, Preuss, Christoph, Burkhard, Silja, Cote, Jean-Marc, Houde, Christine, Castilloux, Julie, Piche, Jessica, Gosset, Natacha, Leclerc, Severine, Wuennemann, Florian, Thibeault, Maryse, Gagnon, Carmen, Galli, Antonella, Tuck, Elizabeth, Hickson, Gilles R., El Amine, Nour, Boufaied, Ines, Lemyre, Emmanuelle, Barbara, Pascal de Santa, Faure, Sandrine, Jonzon, Anders, Cameron, Michel, Dietz, Harry C., Gallo-McFarlane, Elena, Benson, D. Woodrow, Moreau, Claudia, Labuda, Damian, Zhan, Shing H., Shen, Yaoqing, Jomphe, Michele, Jones, Steven J. M., Bakkers, Jeroen, Andelfinger, Gregor, Chetaille, Philippe, Preuss, Christoph, Burkhard, Silja, Cote, Jean-Marc, Houde, Christine, Castilloux, Julie, Piche, Jessica, Gosset, Natacha, Leclerc, Severine, Wuennemann, Florian, Thibeault, Maryse, Gagnon, Carmen, Galli, Antonella, Tuck, Elizabeth, Hickson, Gilles R., El Amine, Nour, Boufaied, Ines, Lemyre, Emmanuelle, Barbara, Pascal de Santa, Faure, Sandrine, Jonzon, Anders, Cameron, Michel, Dietz, Harry C., Gallo-McFarlane, Elena, Benson, D. Woodrow, Moreau, Claudia, Labuda, Damian, Zhan, Shing H., Shen, Yaoqing, Jomphe, Michele, Jones, Steven J. M., Bakkers, Jeroen, and Andelfinger, Gregor

Abstract

The pacemaking activity of specialized tissues in the heart and gut results in lifelong rhythmic contractions. Here we describe a new syndrome characterized by Chronic Atrial and Intestinal Dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Swede. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycle progression, a higher rate of senescence and enhanced activation of TGF-beta signaling. Karyotypes showed the typical railroad appearance of a centromeric cohesion defect. Tissues derived from affected individuals displayed pathological changes in both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the abnormalities seen in humans with CAID syndrome. Our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm.

Published
2014
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