30 results on '"van der Linden, Reinier"'
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2. Single-cell sortChIC identifies hierarchical chromatin dynamics during hematopoiesis
- Author
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Zeller, Peter, Yeung, Jake, Viñas Gaza, Helena, de Barbanson, Buys Anton, Bhardwaj, Vivek, Florescu, Maria, van der Linden, Reinier, van Oudenaarden, Alexander, Zeller, Peter, Yeung, Jake, Viñas Gaza, Helena, de Barbanson, Buys Anton, Bhardwaj, Vivek, Florescu, Maria, van der Linden, Reinier, and van Oudenaarden, Alexander
- Abstract
Post-translational histone modifications modulate chromatin activity to affect gene expression. How chromatin states underlie lineage choice in single cells is relatively unexplored. We develop sort-assisted single-cell chromatin immunocleavage (sortChIC) and map active (H3K4me1 and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in the mouse bone marrow. During differentiation, hematopoietic stem and progenitor cells (HSPCs) acquire active chromatin states mediated by cell-type-specifying transcription factors, which are unique for each lineage. By contrast, most alterations in repressive marks during differentiation occur independent of the final cell type. Chromatin trajectory analysis shows that lineage choice at the chromatin level occurs at the progenitor stage. Joint profiling of H3K4me1 and H3K9me3 demonstrates that cell types within the myeloid lineage have distinct active chromatin but share similar myeloid-specific heterochromatin states. This implies a hierarchical regulation of chromatin during hematopoiesis: heterochromatin dynamics distinguish differentiation trajectories and lineages, while euchromatin dynamics reflect cell types within lineages.
- Published
- 2023
3. Single-cell sortChIC identifies hierarchical chromatin dynamics during hematopoiesis
- Author
-
Zeller, Peter, Yeung, Jake, Viñas Gaza, Helena, de Barbanson, Buys Anton, Bhardwaj, Vivek, Florescu, Maria, van der Linden, Reinier, van Oudenaarden, Alexander, Zeller, Peter, Yeung, Jake, Viñas Gaza, Helena, de Barbanson, Buys Anton, Bhardwaj, Vivek, Florescu, Maria, van der Linden, Reinier, and van Oudenaarden, Alexander
- Abstract
Post-translational histone modifications modulate chromatin activity to affect gene expression. How chromatin states underlie lineage choice in single cells is relatively unexplored. We develop sort-assisted single-cell chromatin immunocleavage (sortChIC) and map active (H3K4me1 and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in the mouse bone marrow. During differentiation, hematopoietic stem and progenitor cells (HSPCs) acquire active chromatin states mediated by cell-type-specifying transcription factors, which are unique for each lineage. By contrast, most alterations in repressive marks during differentiation occur independent of the final cell type. Chromatin trajectory analysis shows that lineage choice at the chromatin level occurs at the progenitor stage. Joint profiling of H3K4me1 and H3K9me3 demonstrates that cell types within the myeloid lineage have distinct active chromatin but share similar myeloid-specific heterochromatin states. This implies a hierarchical regulation of chromatin during hematopoiesis: heterochromatin dynamics distinguish differentiation trajectories and lineages, while euchromatin dynamics reflect cell types within lineages.
- Published
- 2023
4. Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation
- Author
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Lin, Lin, DeMartino, Jeff, Wang, Daisong, van Son, Gijs J F, van der Linden, Reinier, Begthel, Harry, Korving, Jeroen, Andersson-Rolf, Amanda, van den Brink, Stieneke, Lopez-Iglesias, Carmen, van de Wetering, Willine J, Balwierz, Aleksandra, Margaritis, Thanasis, van de Wetering, Marc, Peters, Peter J, Drost, Jarno, van Es, Johan H, Clevers, Hans, Lin, Lin, DeMartino, Jeff, Wang, Daisong, van Son, Gijs J F, van der Linden, Reinier, Begthel, Harry, Korving, Jeroen, Andersson-Rolf, Amanda, van den Brink, Stieneke, Lopez-Iglesias, Carmen, van de Wetering, Willine J, Balwierz, Aleksandra, Margaritis, Thanasis, van de Wetering, Marc, Peters, Peter J, Drost, Jarno, van Es, Johan H, and Clevers, Hans
- Abstract
Enteroendocrine cells (EECs) are hormone-producing cells residing in the epithelium of stomach, small intestine (SI), and colon. EECs regulate aspects of metabolic activity, including insulin levels, satiety, gastrointestinal secretion, and motility. The generation of different EEC lineages is not completely understood. In this work, we report a CRISPR knockout screen of the entire repertoire of transcription factors (TFs) in adult human SI organoids to identify dominant TFs controlling EEC differentiation. We discovered ZNF800 as a master repressor for endocrine lineage commitment, which particularly restricts enterochromaffin cell differentiation by directly controlling an endocrine TF network centered on PAX4. Thus, organoid models allow unbiased functional CRISPR screens for genes that program cell fate.
- Published
- 2023
5. Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation
- Author
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Groep Holstege, Hubrecht Institute with UMC, CMM, Cancer, Lin, Lin, DeMartino, Jeff, Wang, Daisong, van Son, Gijs J.F., van der Linden, Reinier, Begthel, Harry, Korving, Jeroen, Andersson-Rolf, Amanda, den Brink, Stieneke van, Lopez-Iglesias, Carmen, van de Wetering, Willine J., Balwierz, Aleksandra, Margaritis, Thanasis, van de Wetering, Marc, Peters, Peter J., Drost, Jarno, van Es, Johan H., Clevers, Hans, Groep Holstege, Hubrecht Institute with UMC, CMM, Cancer, Lin, Lin, DeMartino, Jeff, Wang, Daisong, van Son, Gijs J.F., van der Linden, Reinier, Begthel, Harry, Korving, Jeroen, Andersson-Rolf, Amanda, den Brink, Stieneke van, Lopez-Iglesias, Carmen, van de Wetering, Willine J., Balwierz, Aleksandra, Margaritis, Thanasis, van de Wetering, Marc, Peters, Peter J., Drost, Jarno, van Es, Johan H., and Clevers, Hans
- Published
- 2023
6. Single-cell sortChIC identifies hierarchical chromatin dynamics during hematopoiesis
- Author
-
CMM Sectie Molecular Cancer Research, Cancer, Hubrecht Institute with UMC, Zeller, Peter, Yeung, Jake, Viñas Gaza, Helena, de Barbanson, Buys Anton, Bhardwaj, Vivek, Florescu, Maria, van der Linden, Reinier, van Oudenaarden, Alexander, CMM Sectie Molecular Cancer Research, Cancer, Hubrecht Institute with UMC, Zeller, Peter, Yeung, Jake, Viñas Gaza, Helena, de Barbanson, Buys Anton, Bhardwaj, Vivek, Florescu, Maria, van der Linden, Reinier, and van Oudenaarden, Alexander
- Published
- 2023
7. Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation
- Author
-
Lin, Lin, DeMartino, Jeff, Wang, Daisong, van Son, Gijs J.F., van der Linden, Reinier, Begthel, Harry, Korving, Jeroen, Andersson-Rolf, Amanda, van den Brink, Stieneke, Lopez-Iglesias, Carmen, van de Wetering, Willine J., Balwierz, Aleksandra, Margaritis, Thanasis, van de Wetering, Marc, Peters, Peter J., Drost, Jarno, van Es, Johan H., Clevers, Hans, Lin, Lin, DeMartino, Jeff, Wang, Daisong, van Son, Gijs J.F., van der Linden, Reinier, Begthel, Harry, Korving, Jeroen, Andersson-Rolf, Amanda, van den Brink, Stieneke, Lopez-Iglesias, Carmen, van de Wetering, Willine J., Balwierz, Aleksandra, Margaritis, Thanasis, van de Wetering, Marc, Peters, Peter J., Drost, Jarno, van Es, Johan H., and Clevers, Hans
- Abstract
Enteroendocrine cells (EECs) are hormone-producing cells residing in the epithelium of stomach, small intestine (SI), and colon. EECs regulate aspects of metabolic activity, including insulin levels, satiety, gastrointestinal secretion, and motility. The generation of different EEC lineages is not completely understood. In this work, we report a CRISPR knockout screen of the entire repertoire of transcription factors (TFs) in adult human SI organoids to identify dominant TFs controlling EEC differentiation. We discovered ZNF800 as a master repressor for endocrine lineage commitment, which particularly restricts enterochromaffin cell differentiation by directly controlling an endocrine TF network centered on PAX4. Thus, organoid models allow unbiased functional CRISPR screens for genes that program cell fate.
- Published
- 2023
8. PDGFR beta(+) cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny
- Author
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da Bandeira, Diana Sa, Kilpatrick, Alastair Morris, Marques, Madalena, Gomez-Salazar, Mario, Ventura, Telma, Gonzalez, Zaniah Nashira, Stefancova, Dorota, Rossi, Fiona, Vermeren, Matthieu, Vink, Chris Sebastiaan, Beltran, Mariana, Henderson, Neil Cowan, Jung, Bongnam, van der Linden, Reinier, van de Werken, Harmen Jan George, van Ijcken, Wilfred F. J., Betsholtz, Christer, Forbes, Stuart John, Cuervo, Henar, Crisan, Mihaela, da Bandeira, Diana Sa, Kilpatrick, Alastair Morris, Marques, Madalena, Gomez-Salazar, Mario, Ventura, Telma, Gonzalez, Zaniah Nashira, Stefancova, Dorota, Rossi, Fiona, Vermeren, Matthieu, Vink, Chris Sebastiaan, Beltran, Mariana, Henderson, Neil Cowan, Jung, Bongnam, van der Linden, Reinier, van de Werken, Harmen Jan George, van Ijcken, Wilfred F. J., Betsholtz, Christer, Forbes, Stuart John, Cuervo, Henar, and Crisan, Mihaela
- Abstract
Hematopoietic stem cell (HSC) generation in the aorta-gonad-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFR beta signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFR beta is involved. Here, we show that PDGFR beta is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFR beta(+) cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFR beta(+) embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of HSPCs in vitro.
- Published
- 2022
- Full Text
- View/download PDF
9. PDGFR beta(+) cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny
- Author
-
da Bandeira, Diana Sa, Kilpatrick, Alastair Morris, Marques, Madalena, Gomez-Salazar, Mario, Ventura, Telma, Gonzalez, Zaniah Nashira, Stefancova, Dorota, Rossi, Fiona, Vermeren, Matthieu, Vink, Chris Sebastiaan, Beltran, Mariana, Henderson, Neil Cowan, Jung, Bongnam, van der Linden, Reinier, van de Werken, Harmen Jan George, van Ijcken, Wilfred F. J., Betsholtz, Christer, Forbes, Stuart John, Cuervo, Henar, Crisan, Mihaela, da Bandeira, Diana Sa, Kilpatrick, Alastair Morris, Marques, Madalena, Gomez-Salazar, Mario, Ventura, Telma, Gonzalez, Zaniah Nashira, Stefancova, Dorota, Rossi, Fiona, Vermeren, Matthieu, Vink, Chris Sebastiaan, Beltran, Mariana, Henderson, Neil Cowan, Jung, Bongnam, van der Linden, Reinier, van de Werken, Harmen Jan George, van Ijcken, Wilfred F. J., Betsholtz, Christer, Forbes, Stuart John, Cuervo, Henar, and Crisan, Mihaela
- Abstract
Hematopoietic stem cell (HSC) generation in the aorta-gonad-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFR beta signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFR beta is involved. Here, we show that PDGFR beta is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFR beta(+) cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFR beta(+) embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of HSPCs in vitro.
- Published
- 2022
- Full Text
- View/download PDF
10. PDGFR beta(+) cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny
- Author
-
da Bandeira, Diana Sa, Kilpatrick, Alastair Morris, Marques, Madalena, Gomez-Salazar, Mario, Ventura, Telma, Gonzalez, Zaniah Nashira, Stefancova, Dorota, Rossi, Fiona, Vermeren, Matthieu, Vink, Chris Sebastiaan, Beltran, Mariana, Henderson, Neil Cowan, Jung, Bongnam, van der Linden, Reinier, van de Werken, Harmen Jan George, van Ijcken, Wilfred F. J., Betsholtz, Christer, Forbes, Stuart John, Cuervo, Henar, Crisan, Mihaela, da Bandeira, Diana Sa, Kilpatrick, Alastair Morris, Marques, Madalena, Gomez-Salazar, Mario, Ventura, Telma, Gonzalez, Zaniah Nashira, Stefancova, Dorota, Rossi, Fiona, Vermeren, Matthieu, Vink, Chris Sebastiaan, Beltran, Mariana, Henderson, Neil Cowan, Jung, Bongnam, van der Linden, Reinier, van de Werken, Harmen Jan George, van Ijcken, Wilfred F. J., Betsholtz, Christer, Forbes, Stuart John, Cuervo, Henar, and Crisan, Mihaela
- Abstract
Hematopoietic stem cell (HSC) generation in the aorta-gonad-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFR beta signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFR beta is involved. Here, we show that PDGFR beta is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFR beta(+) cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFR beta(+) embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of HSPCs in vitro.
- Published
- 2022
- Full Text
- View/download PDF
11. PDGFR beta(+) cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny
- Author
-
da Bandeira, Diana Sa, Kilpatrick, Alastair Morris, Marques, Madalena, Gomez-Salazar, Mario, Ventura, Telma, Gonzalez, Zaniah Nashira, Stefancova, Dorota, Rossi, Fiona, Vermeren, Matthieu, Vink, Chris Sebastiaan, Beltran, Mariana, Henderson, Neil Cowan, Jung, Bongnam, van der Linden, Reinier, van de Werken, Harmen Jan George, van Ijcken, Wilfred F. J., Betsholtz, Christer, Forbes, Stuart John, Cuervo, Henar, Crisan, Mihaela, da Bandeira, Diana Sa, Kilpatrick, Alastair Morris, Marques, Madalena, Gomez-Salazar, Mario, Ventura, Telma, Gonzalez, Zaniah Nashira, Stefancova, Dorota, Rossi, Fiona, Vermeren, Matthieu, Vink, Chris Sebastiaan, Beltran, Mariana, Henderson, Neil Cowan, Jung, Bongnam, van der Linden, Reinier, van de Werken, Harmen Jan George, van Ijcken, Wilfred F. J., Betsholtz, Christer, Forbes, Stuart John, Cuervo, Henar, and Crisan, Mihaela
- Abstract
Hematopoietic stem cell (HSC) generation in the aorta-gonad-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFR beta signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFR beta is involved. Here, we show that PDGFR beta is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFR beta(+) cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFR beta(+) embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of HSPCs in vitro.
- Published
- 2022
- Full Text
- View/download PDF
12. Single-cell sortChIC identifies hierarchical chromatin dynamics during hematopoiesis
- Author
-
Zeller, Peter, Yeung, Jake, Viñas Gaza, Helena, de Barbanson, Buys Anton, Bhardwaj, Vivek, Florescu, Maria, van der Linden, Reinier, van Oudenaarden, Alexander, Zeller, Peter, Yeung, Jake, Viñas Gaza, Helena, de Barbanson, Buys Anton, Bhardwaj, Vivek, Florescu, Maria, van der Linden, Reinier, and van Oudenaarden, Alexander
- Abstract
Post-translational histone modifications modulate chromatin activity to affect gene expression. How chromatin states underlie lineage choice in single cells is relatively unexplored. We develop sort-assisted single-cell chromatin immunocleavage (sortChIC) and map active (H3K4me1 and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in the mouse bone marrow. During differentiation, hematopoietic stem and progenitor cells (HSPCs) acquire active chromatin states mediated by cell-type-specifying transcription factors, which are unique for each lineage. By contrast, most alterations in repressive marks during differentiation occur independent of the final cell type. Chromatin trajectory analysis shows that lineage choice at the chromatin level occurs at the progenitor stage. Joint profiling of H3K4me1 and H3K9me3 demonstrates that cell types within the myeloid lineage have distinct active chromatin but share similar myeloid-specific heterochromatin states. This implies a hierarchical regulation of chromatin during hematopoiesis: heterochromatin dynamics distinguish differentiation trajectories and lineages, while euchromatin dynamics reflect cell types within lineages.
- Published
- 2022
13. PDGFR beta(+) cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny
- Author
-
da Bandeira, Diana Sa, Kilpatrick, Alastair Morris, Marques, Madalena, Gomez-Salazar, Mario, Ventura, Telma, Gonzalez, Zaniah Nashira, Stefancova, Dorota, Rossi, Fiona, Vermeren, Matthieu, Vink, Chris Sebastiaan, Beltran, Mariana, Henderson, Neil Cowan, Jung, Bongnam, van der Linden, Reinier, van de Werken, Harmen Jan George, van Ijcken, Wilfred F. J., Betsholtz, Christer, Forbes, Stuart John, Cuervo, Henar, Crisan, Mihaela, da Bandeira, Diana Sa, Kilpatrick, Alastair Morris, Marques, Madalena, Gomez-Salazar, Mario, Ventura, Telma, Gonzalez, Zaniah Nashira, Stefancova, Dorota, Rossi, Fiona, Vermeren, Matthieu, Vink, Chris Sebastiaan, Beltran, Mariana, Henderson, Neil Cowan, Jung, Bongnam, van der Linden, Reinier, van de Werken, Harmen Jan George, van Ijcken, Wilfred F. J., Betsholtz, Christer, Forbes, Stuart John, Cuervo, Henar, and Crisan, Mihaela
- Abstract
Hematopoietic stem cell (HSC) generation in the aorta-gonad-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFR beta signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFR beta is involved. Here, we show that PDGFR beta is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFR beta(+) cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFR beta(+) embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of HSPCs in vitro.
- Published
- 2022
- Full Text
- View/download PDF
14. Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell
- Author
-
Kildisiute, Gerda, Kholosy, Waleed M, Young, Matthew D, Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R, Pacyna, Clarissa N, Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M, Langenberg-Ververgaert, Karin P S, Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C P, Tas, Michelle L, Wijnen, Marc H W A, van Noesel, Max M, Del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C, Haniffa, Muzlifah, Teichmann, Sarah A, Rampling, Dyanne, Sebire, Neil J, He, Xiaoling, de Krijger, Ronald R, Barker, Roger A, Meyer, Kerstin B, Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J, Behjati, Sam, Kildisiute, Gerda, Kholosy, Waleed M, Young, Matthew D, Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R, Pacyna, Clarissa N, Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M, Langenberg-Ververgaert, Karin P S, Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C P, Tas, Michelle L, Wijnen, Marc H W A, van Noesel, Max M, Del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C, Haniffa, Muzlifah, Teichmann, Sarah A, Rampling, Dyanne, Sebire, Neil J, He, Xiaoling, de Krijger, Ronald R, Barker, Roger A, Meyer, Kerstin B, Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J, and Behjati, Sam
- Abstract
Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.
- Published
- 2021
15. Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell
- Author
-
Afd Pharmaceutics, Pharmaceutics, Kildisiute, Gerda, Kholosy, Waleed M, Young, Matthew D, Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R, Pacyna, Clarissa N, Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M, Langenberg-Ververgaert, Karin P S, Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C P, Tas, Michelle L, Wijnen, Marc H W A, van Noesel, Max M, Del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C, Haniffa, Muzlifah, Teichmann, Sarah A, Rampling, Dyanne, Sebire, Neil J, He, Xiaoling, de Krijger, Ronald R, Barker, Roger A, Meyer, Kerstin B, Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J, Behjati, Sam, Afd Pharmaceutics, Pharmaceutics, Kildisiute, Gerda, Kholosy, Waleed M, Young, Matthew D, Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R, Pacyna, Clarissa N, Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M, Langenberg-Ververgaert, Karin P S, Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C P, Tas, Michelle L, Wijnen, Marc H W A, van Noesel, Max M, Del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C, Haniffa, Muzlifah, Teichmann, Sarah A, Rampling, Dyanne, Sebire, Neil J, He, Xiaoling, de Krijger, Ronald R, Barker, Roger A, Meyer, Kerstin B, Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J, and Behjati, Sam
- Published
- 2021
16. Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell
- Author
-
Afd Pharmaceutics, Pharmaceutics, Kildisiute, Gerda, Kholosy, Waleed M, Young, Matthew D, Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R, Pacyna, Clarissa N, Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M, Langenberg-Ververgaert, Karin P S, Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C P, Tas, Michelle L, Wijnen, Marc H W A, van Noesel, Max M, Del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C, Haniffa, Muzlifah, Teichmann, Sarah A, Rampling, Dyanne, Sebire, Neil J, He, Xiaoling, de Krijger, Ronald R, Barker, Roger A, Meyer, Kerstin B, Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J, Behjati, Sam, Afd Pharmaceutics, Pharmaceutics, Kildisiute, Gerda, Kholosy, Waleed M, Young, Matthew D, Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R, Pacyna, Clarissa N, Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M, Langenberg-Ververgaert, Karin P S, Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C P, Tas, Michelle L, Wijnen, Marc H W A, van Noesel, Max M, Del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C, Haniffa, Muzlifah, Teichmann, Sarah A, Rampling, Dyanne, Sebire, Neil J, He, Xiaoling, de Krijger, Ronald R, Barker, Roger A, Meyer, Kerstin B, Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J, and Behjati, Sam
- Published
- 2021
17. Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell
- Author
-
Afd Pharmaceutics, Pharmaceutics, Kildisiute, Gerda, Kholosy, Waleed M, Young, Matthew D, Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R, Pacyna, Clarissa N, Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M, Langenberg-Ververgaert, Karin P S, Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C P, Tas, Michelle L, Wijnen, Marc H W A, van Noesel, Max M, Del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C, Haniffa, Muzlifah, Teichmann, Sarah A, Rampling, Dyanne, Sebire, Neil J, He, Xiaoling, de Krijger, Ronald R, Barker, Roger A, Meyer, Kerstin B, Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J, Behjati, Sam, Afd Pharmaceutics, Pharmaceutics, Kildisiute, Gerda, Kholosy, Waleed M, Young, Matthew D, Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R, Pacyna, Clarissa N, Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M, Langenberg-Ververgaert, Karin P S, Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C P, Tas, Michelle L, Wijnen, Marc H W A, van Noesel, Max M, Del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C, Haniffa, Muzlifah, Teichmann, Sarah A, Rampling, Dyanne, Sebire, Neil J, He, Xiaoling, de Krijger, Ronald R, Barker, Roger A, Meyer, Kerstin B, Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J, and Behjati, Sam
- Published
- 2021
18. Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell
- Author
-
Groep Holstege, CTI Leusen, CMM Groep Burgering, Cancer, Zorgeenheid Kinderchirurgie Medisch, Onderzoek Beeld, Pathologie Pathologen staf, Kildisiute, Gerda, Kholosy, Waleed M., Young, Matthew D., Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R., Pacyna, Clarissa N., Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M., Langenberg-Ververgaert, Karin P.S., Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C.P., Tas, Michelle L., Wijnen, Marc H.W.A., van Noesel, Max M., del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C., Haniffa, Muzlifah, Teichmann, Sarah A., Rampling, Dyanne, Sebire, Neil J., He, Xiaoling, de Krijger, Ronald R., Barker, Roger A., Meyer, Kerstin B., Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J., Behjati, Sam, Groep Holstege, CTI Leusen, CMM Groep Burgering, Cancer, Zorgeenheid Kinderchirurgie Medisch, Onderzoek Beeld, Pathologie Pathologen staf, Kildisiute, Gerda, Kholosy, Waleed M., Young, Matthew D., Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R., Pacyna, Clarissa N., Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M., Langenberg-Ververgaert, Karin P.S., Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C.P., Tas, Michelle L., Wijnen, Marc H.W.A., van Noesel, Max M., del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C., Haniffa, Muzlifah, Teichmann, Sarah A., Rampling, Dyanne, Sebire, Neil J., He, Xiaoling, de Krijger, Ronald R., Barker, Roger A., Meyer, Kerstin B., Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J., and Behjati, Sam
- Published
- 2021
19. High-Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells
- Author
-
Beumer, Joep, Puschhof, Jens, Bauzá-Martinez, Julia, Martínez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R, Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A, Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H, Bar-Ephraim, Yotam E, Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J, van der Linden, Reinier, Peters, Peter J, Heck, Albert J R, Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A, Wu, Wei, Clevers, Hans, Beumer, Joep, Puschhof, Jens, Bauzá-Martinez, Julia, Martínez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R, Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A, Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H, Bar-Ephraim, Yotam E, Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J, van der Linden, Reinier, Peters, Peter J, Heck, Albert J R, Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A, Wu, Wei, and Clevers, Hans
- Abstract
Enteroendocrine cells (EECs) sense intestinal content and release hormones to regulate gastrointestinal activity, systemic metabolism, and food intake. Little is known about the molecular make-up of human EEC subtypes and the regulated secretion of individual hormones. Here, we describe an organoid-based platform for functional studies of human EECs. EEC formation is induced in vitro by transient expression of NEUROG3. A set of gut organoids was engineered in which the major hormones are fluorescently tagged. A single-cell mRNA atlas was generated for the different EEC subtypes, and their secreted products were recorded by mass-spectrometry. We note key differences to murine EECs, including hormones, sensory receptors, and transcription factors. Notably, several hormone-like molecules were identified. Inter-EEC communication is exemplified by secretin-induced GLP-1 secretion. Indeed, individual EEC subtypes carry receptors for various EEC hormones. This study provides a rich resource to study human EEC development and function.
- Published
- 2020
20. High-Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells
- Author
-
Beumer, Joep, Beumer, Joep, Puschhof, Jens, Bauza-Martinez, Julia, Martinez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R., Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A., Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H., Bar-Ephraim, Yotam E., Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J., van der Linden, Reinier, Peters, Peter J., Heck, Albert J. R., Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A., Wu, Wei, Clevers, Hans, Beumer, Joep, Beumer, Joep, Puschhof, Jens, Bauza-Martinez, Julia, Martinez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R., Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A., Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H., Bar-Ephraim, Yotam E., Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J., van der Linden, Reinier, Peters, Peter J., Heck, Albert J. R., Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A., Wu, Wei, and Clevers, Hans
- Abstract
Enteroendocrine cells (EECs) sense intestinal content and release hormones to regulate gastrointestinal activity, systemic metabolism, and food intake. Little is known about the molecular make-up of human EEC subtypes and the regulated secretion of individual hormones. Here, we describe an organoid-based platform for functional studies of human EECs. EEC formation is induced in vitro by transient expression of NEUROG3. A set of gut organoids was engineered in which the major hormones are fluorescently tagged. A single-cell mRNA atlas was generated for the different EEC subtypes, and their secreted products were recorded by mass-spectrometry. We note key differences to murine EECs, including hormones, sensory receptors, and transcription factors. Notably, several hormone-like molecules were identified. Inter-EEC communication is exemplified by secretin-induced GLP-1 secretion. Indeed, individual EEC subtypes carry receptors for various EEC hormones. This study provides a rich resource to study human EEC development and function.
- Published
- 2020
21. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli
- Author
-
Pleguezuelos-Manzano, Cayetano, Puschhof, Jens, Rosendahl Huber, Axel, van Hoeck, Arne, Wood, Henry M, Nomburg, Jason, Gurjao, Carino, Manders, Freek, Dalmasso, Guillaume, Stege, Paul B, Paganelli, Fernanda L, Geurts, Maarten H, Beumer, Joep, Mizutani, Tomohiro, Miao, Yi, van der Linden, Reinier, van der Elst, Stefan, Garcia, K Christopher, Top, Janetta, Willems, Rob J L, Giannakis, Marios, Bonnet, Richard, Quirke, Phil, Meyerson, Matthew, Cuppen, Edwin, van Boxtel, Ruben, Clevers, Hans, Pleguezuelos-Manzano, Cayetano, Puschhof, Jens, Rosendahl Huber, Axel, van Hoeck, Arne, Wood, Henry M, Nomburg, Jason, Gurjao, Carino, Manders, Freek, Dalmasso, Guillaume, Stege, Paul B, Paganelli, Fernanda L, Geurts, Maarten H, Beumer, Joep, Mizutani, Tomohiro, Miao, Yi, van der Linden, Reinier, van der Elst, Stefan, Garcia, K Christopher, Top, Janetta, Willems, Rob J L, Giannakis, Marios, Bonnet, Richard, Quirke, Phil, Meyerson, Matthew, Cuppen, Edwin, van Boxtel, Ruben, and Clevers, Hans
- Abstract
Various species of the intestinal microbiota have been associated with the development of colorectal cancer1,2, but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin3. This compound is believed to alkylate DNA on adenine residues4,5 and induces double-strand breaks in cultured cells3. Here we expose human intestinal organoids to genotoxic pks+ E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.
- Published
- 2020
22. High-Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells
- Author
-
Beumer, Joep, Puschhof, Jens, Bauzá-Martinez, Julia, Martínez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R, Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A, Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H, Bar-Ephraim, Yotam E, Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J, van der Linden, Reinier, Peters, Peter J, Heck, Albert J R, Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A, Wu, Wei, Clevers, Hans, Beumer, Joep, Puschhof, Jens, Bauzá-Martinez, Julia, Martínez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R, Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A, Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H, Bar-Ephraim, Yotam E, Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J, van der Linden, Reinier, Peters, Peter J, Heck, Albert J R, Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A, Wu, Wei, and Clevers, Hans
- Abstract
Enteroendocrine cells (EECs) sense intestinal content and release hormones to regulate gastrointestinal activity, systemic metabolism, and food intake. Little is known about the molecular make-up of human EEC subtypes and the regulated secretion of individual hormones. Here, we describe an organoid-based platform for functional studies of human EECs. EEC formation is induced in vitro by transient expression of NEUROG3. A set of gut organoids was engineered in which the major hormones are fluorescently tagged. A single-cell mRNA atlas was generated for the different EEC subtypes, and their secreted products were recorded by mass-spectrometry. We note key differences to murine EECs, including hormones, sensory receptors, and transcription factors. Notably, several hormone-like molecules were identified. Inter-EEC communication is exemplified by secretin-induced GLP-1 secretion. Indeed, individual EEC subtypes carry receptors for various EEC hormones. This study provides a rich resource to study human EEC development and function.
- Published
- 2020
23. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli
- Author
-
Pleguezuelos-Manzano, Cayetano, Puschhof, Jens, Rosendahl Huber, Axel, van Hoeck, Arne, Wood, Henry M., Nomburg, Jason, Gurjao, Carino, Manders, Freek, Dalmasso, Guillaume, Stege, Paul B., Paganelli, Fernanda L., Geurts, Maarten H., Beumer, Joep, Mizutani, Tomohiro, Miao, Yi, van der Linden, Reinier, van der Elst, Stefan, Ambrose, J. C., Arumugam, P., Baple, E. L., Bleda, M., Boardman-Pretty, F., Boissiere, J. M., Boustred, C. R., Brittain, H., Caulfield, M. J., Chan, G. C., Craig, C. E. H., Daugherty, L. C., de Burca, A., Devereau, A., Elgar, G., Foulger, R. E., Fowler, T., Furió-Tarí, P., Hackett, J. M., Halai, D., Hamblin, A., Henderson, S., Holman, J. E., Hubbard, T. J. P., Ibáñez, K., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, L., Leigh, S. E. A., Leong, I. U. S., Pleguezuelos-Manzano, Cayetano, Puschhof, Jens, Rosendahl Huber, Axel, van Hoeck, Arne, Wood, Henry M., Nomburg, Jason, Gurjao, Carino, Manders, Freek, Dalmasso, Guillaume, Stege, Paul B., Paganelli, Fernanda L., Geurts, Maarten H., Beumer, Joep, Mizutani, Tomohiro, Miao, Yi, van der Linden, Reinier, van der Elst, Stefan, Ambrose, J. C., Arumugam, P., Baple, E. L., Bleda, M., Boardman-Pretty, F., Boissiere, J. M., Boustred, C. R., Brittain, H., Caulfield, M. J., Chan, G. C., Craig, C. E. H., Daugherty, L. C., de Burca, A., Devereau, A., Elgar, G., Foulger, R. E., Fowler, T., Furió-Tarí, P., Hackett, J. M., Halai, D., Hamblin, A., Henderson, S., Holman, J. E., Hubbard, T. J. P., Ibáñez, K., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, L., Leigh, S. E. A., and Leong, I. U. S.
- Published
- 2020
- Full Text
- View/download PDF
24. High-Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells
- Author
-
Beumer, Joep, Puschhof, Jens, Bauzá-Martinez, Julia, Martínez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R, Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A, Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H, Bar-Ephraim, Yotam E, Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J, van der Linden, Reinier, Peters, Peter J, Heck, Albert J R, Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A, Wu, Wei, Clevers, Hans, Beumer, Joep, Puschhof, Jens, Bauzá-Martinez, Julia, Martínez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R, Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A, Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H, Bar-Ephraim, Yotam E, Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J, van der Linden, Reinier, Peters, Peter J, Heck, Albert J R, Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A, Wu, Wei, and Clevers, Hans
- Abstract
Enteroendocrine cells (EECs) sense intestinal content and release hormones to regulate gastrointestinal activity, systemic metabolism, and food intake. Little is known about the molecular make-up of human EEC subtypes and the regulated secretion of individual hormones. Here, we describe an organoid-based platform for functional studies of human EECs. EEC formation is induced in vitro by transient expression of NEUROG3. A set of gut organoids was engineered in which the major hormones are fluorescently tagged. A single-cell mRNA atlas was generated for the different EEC subtypes, and their secreted products were recorded by mass-spectrometry. We note key differences to murine EECs, including hormones, sensory receptors, and transcription factors. Notably, several hormone-like molecules were identified. Inter-EEC communication is exemplified by secretin-induced GLP-1 secretion. Indeed, individual EEC subtypes carry receptors for various EEC hormones. This study provides a rich resource to study human EEC development and function.
- Published
- 2020
25. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli
- Author
-
Pleguezuelos-Manzano, Cayetano, Puschhof, Jens, Rosendahl Huber, Axel, van Hoeck, Arne, Wood, Henry M, Nomburg, Jason, Gurjao, Carino, Manders, Freek, Dalmasso, Guillaume, Stege, Paul B, Paganelli, Fernanda L, Geurts, Maarten H, Beumer, Joep, Mizutani, Tomohiro, Miao, Yi, van der Linden, Reinier, van der Elst, Stefan, Garcia, K Christopher, Top, Janetta, Willems, Rob J L, Giannakis, Marios, Bonnet, Richard, Quirke, Phil, Meyerson, Matthew, Cuppen, Edwin, van Boxtel, Ruben, Clevers, Hans, Pleguezuelos-Manzano, Cayetano, Puschhof, Jens, Rosendahl Huber, Axel, van Hoeck, Arne, Wood, Henry M, Nomburg, Jason, Gurjao, Carino, Manders, Freek, Dalmasso, Guillaume, Stege, Paul B, Paganelli, Fernanda L, Geurts, Maarten H, Beumer, Joep, Mizutani, Tomohiro, Miao, Yi, van der Linden, Reinier, van der Elst, Stefan, Garcia, K Christopher, Top, Janetta, Willems, Rob J L, Giannakis, Marios, Bonnet, Richard, Quirke, Phil, Meyerson, Matthew, Cuppen, Edwin, van Boxtel, Ruben, and Clevers, Hans
- Abstract
Various species of the intestinal microbiota have been associated with the development of colorectal cancer1,2, but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin3. This compound is believed to alkylate DNA on adenine residues4,5 and induces double-strand breaks in cultured cells3. Here we expose human intestinal organoids to genotoxic pks+ E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.
- Published
- 2020
26. High-Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells
- Author
-
Beumer, Joep, Puschhof, Jens, Bauza-Martinez, Julia, Martinez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R., Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A., Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H., Bar-Ephraim, Yotam E., Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J., van der Linden, Reinier, Peters, Peter J., Heck, Albert J. R., Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A., Wu, Wei, Clevers, Hans, Beumer, Joep, Puschhof, Jens, Bauza-Martinez, Julia, Martinez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R., Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A., Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H., Bar-Ephraim, Yotam E., Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J., van der Linden, Reinier, Peters, Peter J., Heck, Albert J. R., Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A., Wu, Wei, and Clevers, Hans
- Abstract
Enteroendocrine cells (EECs) sense intestinal content and release hormones to regulate gastrointestinal activity, systemic metabolism, and food intake. Little is known about the molecular make-up of human EEC subtypes and the regulated secretion of individual hormones. Here, we describe an organoid-based platform for functional studies of human EECs. EEC formation is induced in vitro by transient expression of NEUROG3. A set of gut organoids was engineered in which the major hormones are fluorescently tagged. A single-cell mRNA atlas was generated for the different EEC subtypes, and their secreted products were recorded by mass-spectrometry. We note key differences to murine EECs, including hormones, sensory receptors, and transcription factors. Notably, several hormone-like molecules were identified. Inter-EEC communication is exemplified by secretin-induced GLP-1 secretion. Indeed, individual EEC subtypes carry receptors for various EEC hormones. This study provides a rich resource to study human EEC development and function.
- Published
- 2020
27. High-Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells
- Author
-
CMM Groep Snippert, Cancer, CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, Beumer, Joep, Puschhof, Jens, Bauzá-Martinez, Julia, Martínez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R, Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A, Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H, Bar-Ephraim, Yotam E, Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J, van der Linden, Reinier, Peters, Peter J, Heck, Albert J R, Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A, Wu, Wei, Clevers, Hans, CMM Groep Snippert, Cancer, CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, Beumer, Joep, Puschhof, Jens, Bauzá-Martinez, Julia, Martínez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R, Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A, Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H, Bar-Ephraim, Yotam E, Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J, van der Linden, Reinier, Peters, Peter J, Heck, Albert J R, Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A, Wu, Wei, and Clevers, Hans
- Published
- 2020
28. Cell Type Purification by Single-Cell Transcriptome-Trained Sorting
- Author
-
Baron, Chloé S, Barve, Aditya, Muraro, Mauro J, van der Linden, Reinier, Dharmadhikari, Gitanjali, Lyubimova, Anna, de Koning, Eelco J P, van Oudenaarden, Alexander, Baron, Chloé S, Barve, Aditya, Muraro, Mauro J, van der Linden, Reinier, Dharmadhikari, Gitanjali, Lyubimova, Anna, de Koning, Eelco J P, and van Oudenaarden, Alexander
- Abstract
Much of current molecular and cell biology research relies on the ability to purify cell types by fluorescence-activated cell sorting (FACS). FACS typically relies on the ability to label cell types of interest with antibodies or fluorescent transgenic constructs. However, antibody availability is often limited, and genetic manipulation is labor intensive or impossible in the case of primary human tissue. To date, no systematic method exists to enrich for cell types without a priori knowledge of cell-type markers. Here, we propose GateID, a computational method that combines single-cell transcriptomics with FACS index sorting to purify cell types of choice using only native cellular properties such as cell size, granularity, and mitochondrial content. We validate GateID by purifying various cell types from zebrafish kidney marrow and the human pancreas to high purity without resorting to specific antibodies or transgenes.
- Published
- 2019
29. Cell Type Purification by Single-Cell Transcriptome-Trained Sorting
- Author
-
Baron, Chloé S, Barve, Aditya, Muraro, Mauro J, van der Linden, Reinier, Dharmadhikari, Gitanjali, Lyubimova, Anna, de Koning, Eelco J P, van Oudenaarden, Alexander, Baron, Chloé S, Barve, Aditya, Muraro, Mauro J, van der Linden, Reinier, Dharmadhikari, Gitanjali, Lyubimova, Anna, de Koning, Eelco J P, and van Oudenaarden, Alexander
- Abstract
Much of current molecular and cell biology research relies on the ability to purify cell types by fluorescence-activated cell sorting (FACS). FACS typically relies on the ability to label cell types of interest with antibodies or fluorescent transgenic constructs. However, antibody availability is often limited, and genetic manipulation is labor intensive or impossible in the case of primary human tissue. To date, no systematic method exists to enrich for cell types without a priori knowledge of cell-type markers. Here, we propose GateID, a computational method that combines single-cell transcriptomics with FACS index sorting to purify cell types of choice using only native cellular properties such as cell size, granularity, and mitochondrial content. We validate GateID by purifying various cell types from zebrafish kidney marrow and the human pancreas to high purity without resorting to specific antibodies or transgenes.
- Published
- 2019
30. Cell Type Purification by Single-Cell Transcriptome-Trained Sorting
- Author
-
Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Cancer, Baron, Chloé S., Barve, Aditya, Muraro, Mauro J., van der Linden, Reinier, Dharmadhikari, Gitanjali, Lyubimova, Anna, de Koning, Eelco J.P., van Oudenaarden, Alexander, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Cancer, Baron, Chloé S., Barve, Aditya, Muraro, Mauro J., van der Linden, Reinier, Dharmadhikari, Gitanjali, Lyubimova, Anna, de Koning, Eelco J.P., and van Oudenaarden, Alexander
- Published
- 2019
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