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1. A flexible, image-based, high-throughput platform encompassing in-depth cell profiling to identify broad-spectrum coronavirus antivirals with limited off-target effects

Author

Doijen, Jordi, Heo, Inha, Temmerman, Koen, Vermeulen, Peter, Diels, Annick, Jaensch, Steffen, Burcin, Mark, Van den Broeck, Nick, Raeymaekers, Valerie, Peremans, Joren, Konings, Katrien, Clement, Maxime, Peeters, Danielle, Van Loock, Marnix, Koul, Anil, Buyck, Christophe, Van Gool, Michiel, and Van Damme, Ellen

Published
2024
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3. A flexible, image-based, high-throughput platform encompassing in-depth cell profiling to identify broad-spectrum coronavirus antivirals with limited off-target effects

Author

Doijen, Jordi, primary, Heo, Inha, additional, Temmerman, Koen, additional, Vermeulen, Peter, additional, Diels, Annick, additional, Jaensch, Steffen, additional, Burcin, Mark, additional, Van den Broeck, Nick, additional, Raeymaekers, Valerie, additional, Peremans, Joren, additional, Konings, Katrien, additional, Clement, Maxime, additional, Peeters, Danielle, additional, Van Loock, Marnix, additional, Koul, Anil, additional, Buyck, Christophe, additional, Van Gool, Michiel, additional, and Van Damme, Ellen, additional

Published
2023
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6. Proteomic discovery of chemical probes that perturb protein complexes in human cells

Author

Lazear, Michael R., primary, Remsberg, Jarrett R., additional, Jaeger, Martin G., additional, Rothamel, Katherine, additional, Her, Hsuan-lin, additional, DeMeester, Kristen E., additional, Njomen, Evert, additional, Hogg, Simon J., additional, Rahman, Jahan, additional, Whitby, Landon R., additional, Won, Sang Joon, additional, Schafroth, Michael A., additional, Ogasawara, Daisuke, additional, Yokoyama, Minoru, additional, Lindsey, Garrett L., additional, Li, Haoxin, additional, Germain, Jason, additional, Barbas, Sabrina, additional, Vaughan, Joan, additional, Hanigan, Thomas W., additional, Vartabedian, Vincent F., additional, Reinhardt, Christopher J., additional, Dix, Melissa M., additional, Koo, Seong Joo, additional, Heo, Inha, additional, Teijaro, John R., additional, Simon, Gabriel M., additional, Ghosh, Brahma, additional, Abdel-Wahab, Omar, additional, Ahn, Kay, additional, Saghatelian, Alan, additional, Melillo, Bruno, additional, Schreiber, Stuart L., additional, Yeo, Gene W., additional, and Cravatt, Benjamin F., additional

Published
2023
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7. Identification of Z-Tyr-Ala-CHN 2, a Cathepsin L Inhibitor with Broad-Spectrum Cell-Specific Activity against Coronaviruses, including SARS-CoV-2.

Author

Doijen, Jordi, Temmerman, Koen, Van den Eynde, Christel, Diels, Annick, Van den Broeck, Nick, Van Gool, Michiel, Heo, Inha, Jaensch, Steffen, Zwaagstra, Marleen, Diosa Toro, Mayra, Chiu, Winston, De Jonghe, Steven, Leyssen, Pieter, Bojkova, Denisa, Ciesek, Sandra, Cinatl, Jindrich, Verschueren, Lore, Buyck, Christophe, Van Kuppeveld, Frank, Neyts, Johan, Van Loock, Marnix, Van Damme, Ellen, Doijen, Jordi, Temmerman, Koen, Van den Eynde, Christel, Diels, Annick, Van den Broeck, Nick, Van Gool, Michiel, Heo, Inha, Jaensch, Steffen, Zwaagstra, Marleen, Diosa Toro, Mayra, Chiu, Winston, De Jonghe, Steven, Leyssen, Pieter, Bojkova, Denisa, Ciesek, Sandra, Cinatl, Jindrich, Verschueren, Lore, Buyck, Christophe, Van Kuppeveld, Frank, Neyts, Johan, Van Loock, Marnix, and Van Damme, Ellen

Abstract

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control by vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of severe COVID-19. We report the discovery of a small molecule, Z-Tyr-Ala-CHN 2, which was identified in a cell-based antiviral screen. The molecule exerts sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and human coronavirus 229E. Time-of-addition studies reveal that Z-Tyr-Ala-CHN 2 acts at the early phase of the infection cycle, which is in line with the observation that the molecule inhibits cathepsin L. This results in antiviral activity against SARS-CoV-2 in VeroE6, A549-hACE2, and HeLa-hACE2 cells, but not in Caco-2 cells or primary human nasal epithelial cells since the latter two cell types also permit entry via transmembrane protease serine subtype 2 (TMPRSS2). Given their cell-specific activity, cathepsin L inhibitors still need to prove their value in the clinic; nevertheless, the activity profile of Z-Tyr-Ala-CHN 2 makes it an interesting tool compound for studying the biology of coronavirus entry and replication.

Published
2023

8. Identification of Z-Tyr-Ala-CHN 2, a Cathepsin L Inhibitor with Broad-Spectrum Cell-Specific Activity against Coronaviruses, including SARS-CoV-2.

Author

Virologie, Doijen, Jordi, Temmerman, Koen, Van den Eynde, Christel, Diels, Annick, Van den Broeck, Nick, Van Gool, Michiel, Heo, Inha, Jaensch, Steffen, Zwaagstra, Marleen, Diosa Toro, Mayra, Chiu, Winston, De Jonghe, Steven, Leyssen, Pieter, Bojkova, Denisa, Ciesek, Sandra, Cinatl, Jindrich, Verschueren, Lore, Buyck, Christophe, Van Kuppeveld, Frank, Neyts, Johan, Van Loock, Marnix, Van Damme, Ellen, Virologie, Doijen, Jordi, Temmerman, Koen, Van den Eynde, Christel, Diels, Annick, Van den Broeck, Nick, Van Gool, Michiel, Heo, Inha, Jaensch, Steffen, Zwaagstra, Marleen, Diosa Toro, Mayra, Chiu, Winston, De Jonghe, Steven, Leyssen, Pieter, Bojkova, Denisa, Ciesek, Sandra, Cinatl, Jindrich, Verschueren, Lore, Buyck, Christophe, Van Kuppeveld, Frank, Neyts, Johan, Van Loock, Marnix, and Van Damme, Ellen

Published
2023

9. Identification of Z-Tyr-Ala-CHN2, a cathepsin L inhibitor with broad-spectrum cell-specific activity against coronaviruses, including SARS-CoV-2

Author

Doijen, Jordi, Temmerman, Koen, Eynde, Christel van der, Diels, Annick, Broeck, Nick van der, Gool, Michiel van, Heo, Inha, Jaensch, Steffen, Zwaagstra, Marleen, Diosa Toro, Mayra, Chiu, Winston, De Jonghe, Steven, Leyssen, Pieter, Bojkova, Denisa, Ciesek, Sandra, Cinatl, Jindrich, Verschueren, Lore, Buyck, Christophe, Kuppeveld, Franciscus Johannes Maria van, Neyts, Johan, Loock, Marnix van, Damme, Ellen van, Doijen, Jordi, Temmerman, Koen, Eynde, Christel van der, Diels, Annick, Broeck, Nick van der, Gool, Michiel van, Heo, Inha, Jaensch, Steffen, Zwaagstra, Marleen, Diosa Toro, Mayra, Chiu, Winston, De Jonghe, Steven, Leyssen, Pieter, Bojkova, Denisa, Ciesek, Sandra, Cinatl, Jindrich, Verschueren, Lore, Buyck, Christophe, Kuppeveld, Franciscus Johannes Maria van, Neyts, Johan, Loock, Marnix van, and Damme, Ellen van

Abstract

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control by vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of severe COVID-19. We report the discovery of a small molecule, Z-Tyr-Ala-CHN2, which was identified in a cell-based antiviral screen. The molecule exerts sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and human coronavirus 229E. Time-of-addition studies reveal that Z-Tyr-Ala-CHN2 acts at the early phase of the infection cycle, which is in line with the observation that the molecule inhibits cathepsin L. This results in antiviral activity against SARS-CoV-2 in VeroE6, A549-hACE2, and HeLa-hACE2 cells, but not in Caco-2 cells or primary human nasal epithelial cells since the latter two cell types also permit entry via transmembrane protease serine subtype 2 (TMPRSS2). Given their cell-specific activity, cathepsin L inhibitors still need to prove their value in the clinic; nevertheless, the activity profile of Z-Tyr-Ala-CHN2 makes it an interesting tool compound for studying the biology of coronavirus entry and replication.

Published
2023

10. Long‐term expanding human airway organoids for disease modeling

Author

Sachs, Norman, Papaspyropoulos, Angelos, Zomer‐van Ommen, Domenique D, Heo, Inha, Böttinger, Lena, Klay, Dymph, Weeber, Fleur, Huelsz‐Prince, Guizela, Iakobachvili, Nino, Amatngalim, Gimano D, de Ligt, Joep, van Hoeck, Arne, Proost, Natalie, Viveen, Marco C, Lyubimova, Anna, Teeven, Luc, Derakhshan, Sepideh, Korving, Jeroen, Begthel, Harry, Dekkers, Johanna F, Kumawat, Kuldeep, Ramos, Emilio, van Oosterhout, Matthijs FM, Offerhaus, G Johan, Wiener, Dominique J, Olimpio, Eduardo P, Dijkstra, Krijn K, Smit, Egbert F, van der Linden, Maarten, Jaksani, Sridevi, van de Ven, Marieke, Jonkers, Jos, Rios, Anne C, Voest, Emile E, van Moorsel, Coline HM, van der Ent, Cornelis K, Cuppen, Edwin, van Oudenaarden, Alexander, Coenjaerts, Frank E, Meyaard, Linde, Bont, Louis J, Peters, Peter J, Tans, Sander J, van Zon, Jeroen S, Boj, Sylvia F, Vries, Robert G, Beekman, Jeffrey M, and Clevers, Hans

Published
2019
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11. Identification of Z-Tyr-Ala-CHN2, a Cathepsin L Inhibitor with Broad-Spectrum Cell-Specific Activity against Coronaviruses, including SARS-CoV-2

Author

Doijen, Jordi, primary, Temmerman, Koen, additional, Van den Eynde, Christel, additional, Diels, Annick, additional, Van den Broeck, Nick, additional, Van Gool, Michiel, additional, Heo, Inha, additional, Jaensch, Steffen, additional, Zwaagstra, Marleen, additional, Diosa Toro, Mayra, additional, Chiu, Winston, additional, De Jonghe, Steven, additional, Leyssen, Pieter, additional, Bojkova, Denisa, additional, Ciesek, Sandra, additional, Cinatl, Jindrich, additional, Verschueren, Lore, additional, Buyck, Christophe, additional, Van Kuppeveld, Frank, additional, Neyts, Johan, additional, Van Loock, Marnix, additional, and Van Damme, Ellen, additional

Published
2023
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12. Proteomic discovery of chemical probes that perturb protein complexes in human cells

Author

Lazear, Michael R., primary, Remsberg, Jarrett R., additional, Jaeger, Martin G., additional, Rothamel, Katherine, additional, Her, Hsuan-lin, additional, DeMeester, Kristen E., additional, Njomen, Evert, additional, Hogg, Simon J., additional, Rahman, Jahan, additional, Whitby, Landon R., additional, Won, Sang Joon, additional, Schafroth, Michael A., additional, Ogasawara, Daisuke, additional, Yokoyama, Minoru, additional, Lindsey, Garrett L., additional, Li, Haoxin, additional, Germain, Jason, additional, Barbas, Sabrina, additional, Vaughan, Joan, additional, Hanigan, Thomas W., additional, Vartabedian, Vincent F., additional, Reinhardt, Christopher J., additional, Dix, Melissa M., additional, Koo, Seong Joo, additional, Heo, Inha, additional, Teijaro, John R., additional, Simon, Gabriel M., additional, Ghosh, Brahma, additional, Abdel-Wahab, Omar, additional, Ahn, Kay, additional, Saghatelian, Alan, additional, Melillo, Bruno, additional, Schreiber, Stuart L., additional, Yeo, Gene W., additional, and Cravatt, Benjamin F., additional

Published
2022
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14. Intestinal organoid cocultures with microbes

Author

Hubrecht Institute with UMC, Puschhof, Jens, Pleguezuelos-Manzano, Cayetano, Martinez-Silgado, Adriana, Akkerman, Ninouk, Saftien, Aurelia, Boot, Charelle, de Waal, Amy, Beumer, Joep, Dutta, Devanjali, Heo, Inha, Clevers, Hans, Hubrecht Institute with UMC, Puschhof, Jens, Pleguezuelos-Manzano, Cayetano, Martinez-Silgado, Adriana, Akkerman, Ninouk, Saftien, Aurelia, Boot, Charelle, de Waal, Amy, Beumer, Joep, Dutta, Devanjali, Heo, Inha, and Clevers, Hans

Published
2021

16. Dicer recognizes the 5' end of RNA for efficient and accurate processing

Author

Heo, Inha, Tian, Yuan, Simanshu, Dhirendra K., Chang, Hyeshik, Jee, David, Patel, Dinshaw J., and Kim, V. Narry

Subjects
RNA -- Physiological aspects -- Health aspects, Proteins -- Physiological aspects -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A hallmark of RNA silencing is a class of approximately 22-nucleotide RNAs that are processed from double-stranded RNA precursors by Dicer. Accurate processing by Dicer is crucial for the functionality of microRNAs (miRNAs). The current model posits that Dicer selects cleavage sites by measuring a set distance from the 3' overhang of the double-stranded RNA terminus. Here we report that human Dicer anchors not only the 39 end but also the 59 end, with the cleavage site determined mainly by the distance (~22 nucleotides) from the 5' end (5' counting rule). This cleavage requires a 5'-terminal phosphate group. Further, we identify a novel basic motif (5' pocket) in human Dicer that recognizes the 5'-phosphorylated end. The 5' counting rule and the 5' anchoring residues are conserved in Drosophila Dicer-1, but not in Giardia Dicer. Mutations in the 5' pocket reduce processing efficiency and alter cleavage sites in vitro. Consistently, miRNA biogenesis is perturbed in vivo when Dicer-null embryonic stem cells are replenished with the 5'-pocket mutant. Thus, 5'-end recognition by Dicer is important for precise and effective biogenesis of miRNAs. Insights from this study should also afford practical benefits to the design of small hairpin RNAs., RNase III proteins have central roles in RNA silencing by processing double-stranded (ds)RNA precursors into small RNA duplexes (1). Drosha cleaves a primary precursor of miRNA (pri-miRNA) to release a [...]

Published
2011
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17. Modifications of Small RNAs and Their Associated Proteins

Author

Kim, Young-Kook, Heo, Inha, and Kim, V. Narry

Subjects
Proteins, Biological sciences
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.11.018 Byline: Young-Kook Kim (1), Inha Heo (1), V. Narry Kim (1) Abstract: Small regulatory RNAs and their associated proteins are subject to diverse modifications that can impinge on their abundance and function. Some of the modifications are under the influence of cellular signaling, thus contributing to the dynamic regulation of RNA silencing. Author Affiliation: (1) School of Biological Sciences and Center for National Creative Research, Seoul National University, Seoul 151-742, Korea

Published
2010

18. Regulating the Regulators: Posttranslational Modifications of RNA Silencing Factors

Author

Heo, Inha and Kim, V. Narry

Subjects
RNA, Biological sciences
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.09.013 Byline: Inha Heo (1), V. Narry Kim (1) Abstract: Every regulator should be regulated, and this holds true for small RNAs and their associated proteins. Knowledge has begun to emerge of the various mechanisms that impose specificity on the expression and function of RNA silencing factors. Recent papers, including one in this issue of Cell (), now reveal the posttranslational modifications that take part in the regulation of the core RNA silencing factors, Ago, Piwi, and TRBP. Author Affiliation: (1) School of Biological Sciences and National Creative Research Initiatives Center, Seoul National University, Seoul 151-742, Korea

Published
2009

19. TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation

Author

Heo, Inha, Joo, Chirlmin, Kim, Young-Kook, Ha, Minju, Yoon, Mi-Jeong, Cho, Jun, Yeom, Kyu-Hyeon, Han, Jinju, and Kim, V. Narry

Subjects
Cancer -- Research, Oncology, Experimental, Stem cells, Stem cell research, RNA, Enzymes, Concerts, Biological sciences
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.08.002 Byline: Inha Heo (1), Chirlmin Joo (1), Young-Kook Kim (1), Minju Ha (1), Mi-Jeong Yoon (1), Jun Cho (1), Kyu-Hyeon Yeom (1), Jinju Han (1), V. Narry Kim (1) Keywords: RNA; PROTEINS; STEMCELL Abstract: As key regulators in cellular functions, microRNAs (miRNAs) themselves need to be tightly controlled. Lin28, a pluripotency factor, was reported to downregulate let-7 miRNA by inducing uridylation of let-7 precursor (pre-let-7). But the enzyme responsible for the uridylation remained unknown. Here we identify a noncanonical poly (A) polymerase, TUTase4 (TUT4), as the uridylyl transferase for pre-let-7. Lin28 recruits TUT4 to pre-let-7 by recognizing a tetra-nucleotide sequence motif (GGAG) in the terminal loop. TUT4 in turn adds an oligouridine tail to the pre-let-7, which blocks Dicer processing. Other miRNAs with the same sequence motif (miR-107, -143, and -200c) are regulated through the same mechanism. Knockdown of TUT4 and Lin28 reduces the level of stem cell markers, suggesting that they are required for stem cell maintenance. This study uncovers the role of TUT4 and Lin28 as specific suppressors of miRNA biogenesis, which has implications for stem cell research and cancer biology. Author Affiliation: (1) Creative Research Center and School of Biological Sciences, Seoul National University, Seoul, Korea 151-742 Article History: Received 6 April 2009; Revised 16 June 2009; Accepted 3 August 2009 Article Note: (miscellaneous) Published: August 20, 2009

Published
2009

22. Studying Cryptosporidium Infection in 3D Tissue-derived Human Organoid Culture Systems by Microinjection

Author

Dutta, Devanjali, Heo, Inha, and O'Connor, Roberta

Subjects
Biochemistry, Genetics and Molecular Biology(all), Neuroscience(all), Immunology and Microbiology(all), Chemical Engineering(all)
Abstract

Cryptosporidium parvum is one of the major causes of human diarrheal disease. To understand the pathology of the parasite and develop efficient drugs, an in vitro culture system that recapitulates the conditions in the host is needed. Organoids, which closely resemble the tissues of their origin, are ideal for studying host-parasite interactions. Organoids are three-dimensional (3D) tissue-derived structures which are derived from adult stem cells and grow in culture for extended periods of time without undergoing any genetic aberration or transformation. They have well defined polarity with both apical and basolateral surfaces. Organoids have various applications in drug testing, bio banking, and disease modeling and host-microbe interaction studies. Here we present a step-by-step protocol of how to prepare the oocysts and sporozoites of Cryptosporidium for infecting human intestinal and airway organoids. We then demonstrate how microinjection can be used to inject the microbes into the organoid lumen. There are three major methods by which organoids can be used for host-microbe interaction studies-microinjection, mechanical shearing and plating, and by making monolayers. Microinjection enables maintenance of the 3D structure and allows for precise control of parasite volumes and direct apical side contact for the microbes. We provide details for optimal growth of organoids for either imaging or oocyst production. Finally, we also demonstrate how the newly generated oocysts can be isolated from the organoid for further downstream processing and analysis.

Published
2019

23. Probing the Tumor Suppressor Function of BAP1 in CRISPR-Engineered Human Liver Organoids

Author

Artegiani, Benedetta, Artegiani, Benedetta, van Voorthuijsen, Lisa, Lindeboom, Rik G. H., Seinstra, Danielle, Heo, Inha, Tapia, Pablo, Lopez-Iglesias, Carmen, Postrach, Daniel, Dayton, Talya, Oka, Rurika, Hu, Huili, van Boxtel, Ruben, van Es, Johan H., Offerhaus, Johan, Peters, Peter J., van Rheenen, Jacco, Vermeulen, Michiel, Clevers, Hans, Artegiani, Benedetta, Artegiani, Benedetta, van Voorthuijsen, Lisa, Lindeboom, Rik G. H., Seinstra, Danielle, Heo, Inha, Tapia, Pablo, Lopez-Iglesias, Carmen, Postrach, Daniel, Dayton, Talya, Oka, Rurika, Hu, Huili, van Boxtel, Ruben, van Es, Johan H., Offerhaus, Johan, Peters, Peter J., van Rheenen, Jacco, Vermeulen, Michiel, and Clevers, Hans

Abstract

The deubiquitinating enzyme BAP1 is a tumor suppressor, among others involved in cholangiocarcinoma. BAP1 has many proposed molecular targets, while its Drosophila homolog is known to deubiquitinate histone H2AK119. We introduce BAP1 loss-of-function by CRISPR/Cas9 in normal human cholangiocyte organoids. We find that BAP1 controls the expression of junctional and cytoskeleton components by regulating chromatin accessibility. Consequently, we observe loss of multiple epithelial characteristics while motility increases. Importantly, restoring the catalytic activity of BAP1 in the nucleus rescues these cellular and molecular changes. We engineer human liver organoids to combine four common cholangiocarcinoma mutations (TP53, PTEN, SMAD4, and NF1). In this genetic background, BAP1 loss results in acquisition of malignant features upon xenotransplantation. Thus, control of epithelial identity through the regulation of chromatin accessibility appears to be a key aspect of BAP1's tumor suppressor function. Organoid technology combined with CRISPR/Cas9 provides an experimental platform for mechanistic studies of cancer gene function in a human context.

Published
2019

25. Long-term expanding human airway organoids for disease modeling

Author

Longziekten onderzoek 2, Child Health, Onderzoek Longziekten, Externen Med. Onco, CMM Groep De Ridder, Cancer, CMM Groep Cuppen, MMB, CTI Bont, Pathologie Pathologen staf, MS Medische Oncologie, CTI Meyaard, Researchafd. Longtransplantatie, CMM, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, MMB Research line 3a, Infection & Immunity, CTI, Infectiezieken, Infectieziekten onderzoek1 (Bont), Onderzoek, Regenerative Medicine and Stem Cells, Sachs, Norman, Papaspyropoulos, Angelos, Zomer-van Ommen, Domenique D., Heo, Inha, Böttinger, Lena, Klay, Dymph, Weeber, Fleur, Huelsz-Prince, Guizela, Iakobachvili, Nino, Amatngalim, Gimano D., de Ligt, Joep, van Hoeck, Arne, Proost, Natalie, Viveen, Marco C., Lyubimova, Anna, Teeven, Luc, Derakhshan, Sepideh, Korving, Jeroen, Begthel, Harry, Dekkers, Johanna F., Kumawat, Kuldeep, Ramos, Emilio, van Oosterhout, Matthijs F.M., Offerhaus, G. Johan, Wiener, Dominique J., Olimpio, Eduardo P., Dijkstra, Krijn K., Smit, Egbert F., van der Linden, Maarten, Jaksani, Sridevi, van de Ven, Marieke, Jonkers, Jos, Rios, Anne C., Voest, Emile E., van Moorsel, Coline H.M., van der Ent, Cornelis K., Cuppen, Edwin, van Oudenaarden, Alexander, Coenjaerts, Frank E., Meyaard, Linde, Bont, Louis J., Peters, Peter J., Tans, Sander J., van Zon, Jeroen S., Boj, Sylvia F., Vries, Robert G., Beekman, Jeffrey M., Clevers, Hans, Longziekten onderzoek 2, Child Health, Onderzoek Longziekten, Externen Med. Onco, CMM Groep De Ridder, Cancer, CMM Groep Cuppen, MMB, CTI Bont, Pathologie Pathologen staf, MS Medische Oncologie, CTI Meyaard, Researchafd. Longtransplantatie, CMM, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, MMB Research line 3a, Infection & Immunity, CTI, Infectiezieken, Infectieziekten onderzoek1 (Bont), Onderzoek, Regenerative Medicine and Stem Cells, Sachs, Norman, Papaspyropoulos, Angelos, Zomer-van Ommen, Domenique D., Heo, Inha, Böttinger, Lena, Klay, Dymph, Weeber, Fleur, Huelsz-Prince, Guizela, Iakobachvili, Nino, Amatngalim, Gimano D., de Ligt, Joep, van Hoeck, Arne, Proost, Natalie, Viveen, Marco C., Lyubimova, Anna, Teeven, Luc, Derakhshan, Sepideh, Korving, Jeroen, Begthel, Harry, Dekkers, Johanna F., Kumawat, Kuldeep, Ramos, Emilio, van Oosterhout, Matthijs F.M., Offerhaus, G. Johan, Wiener, Dominique J., Olimpio, Eduardo P., Dijkstra, Krijn K., Smit, Egbert F., van der Linden, Maarten, Jaksani, Sridevi, van de Ven, Marieke, Jonkers, Jos, Rios, Anne C., Voest, Emile E., van Moorsel, Coline H.M., van der Ent, Cornelis K., Cuppen, Edwin, van Oudenaarden, Alexander, Coenjaerts, Frank E., Meyaard, Linde, Bont, Louis J., Peters, Peter J., Tans, Sander J., van Zon, Jeroen S., Boj, Sylvia F., Vries, Robert G., Beekman, Jeffrey M., and Clevers, Hans

Published
2019

26. Probing the Tumor Suppressor Function of BAP1 in CRISPR-Engineered Human Liver Organoids

Author

CMM Groep Cuppen, Hubrecht Institute with UMC, Pathologie Groep Moelans, UMC Utrecht Holding, Pathologie Pathologen staf, Cancer, CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Artegiani, Benedetta, van Voorthuijsen, Lisa, Lindeboom, Rik G.H., Seinstra, Daniëlle, Heo, Inha, Tapia, Pablo, López-Iglesias, Carmen, Postrach, Daniel, Dayton, Talya, Oka, Rurika, Hu, Huili, van Boxtel, Ruben, van Es, Johan H., Offerhaus, Johan, Peters, Peter J., van Rheenen, Jacco, Vermeulen, Michiel, Clevers, Hans, CMM Groep Cuppen, Hubrecht Institute with UMC, Pathologie Groep Moelans, UMC Utrecht Holding, Pathologie Pathologen staf, Cancer, CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Artegiani, Benedetta, van Voorthuijsen, Lisa, Lindeboom, Rik G.H., Seinstra, Daniëlle, Heo, Inha, Tapia, Pablo, López-Iglesias, Carmen, Postrach, Daniel, Dayton, Talya, Oka, Rurika, Hu, Huili, van Boxtel, Ruben, van Es, Johan H., Offerhaus, Johan, Peters, Peter J., van Rheenen, Jacco, Vermeulen, Michiel, and Clevers, Hans

Published
2019

27. Probing the Tumor Suppressor Function of BAP1 in CRISPR-Engineered Human Liver Organoids

Author

Artegiani, Benedetta, primary, van Voorthuijsen, Lisa, additional, Lindeboom, Rik G.H., additional, Seinstra, Daniëlle, additional, Heo, Inha, additional, Tapia, Pablo, additional, López-Iglesias, Carmen, additional, Postrach, Daniel, additional, Dayton, Talya, additional, Oka, Rurika, additional, Hu, Huili, additional, van Boxtel, Ruben, additional, van Es, Johan H., additional, Offerhaus, Johan, additional, Peters, Peter J., additional, van Rheenen, Jacco, additional, Vermeulen, Michiel, additional, and Clevers, Hans, additional

Published
2019
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28. Modelling Cryptosporidium infection in human small intestinal and lung organoids

Author

MMB Research Algemeen, Infection & Immunity, CMM Sectie Molecular Cancer Research, Cancer, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, Heo, Inha, Dutta, Devanjali, Schaefer, Deborah A., Iakobachvili, Nino, Artegiani, Benedetta, Sachs, Norman, Boonekamp, Kim E., Bowden, Gregory, Hendrickx, Antoni P.A., Willems, Robert J.L., Peters, Peter J., Riggs, Michael W., O'Connor, Roberta, Clevers, Hans, MMB Research Algemeen, Infection & Immunity, CMM Sectie Molecular Cancer Research, Cancer, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, Heo, Inha, Dutta, Devanjali, Schaefer, Deborah A., Iakobachvili, Nino, Artegiani, Benedetta, Sachs, Norman, Boonekamp, Kim E., Bowden, Gregory, Hendrickx, Antoni P.A., Willems, Robert J.L., Peters, Peter J., Riggs, Michael W., O'Connor, Roberta, and Clevers, Hans

Published
2018

29. Long-term expanding human airway organoids for disease modelling

Author

Sachs, Norman, primary, Zomer-van Ommen, Domenique D., additional, Papaspyropoulos, Angelos, additional, Heo, Inha, additional, Böttinger, Lena, additional, Klay, Dymph, additional, Weeber, Fleur, additional, Huelsz-Prince, Guizela, additional, Iakobachvili, Nino, additional, Viveen, Marco C., additional, Lyubimova, Anna, additional, Teeven, Luc, additional, Derakhshan, Sepideh, additional, Korving, Jeroen, additional, Begthel, Harry, additional, Kumawat, Kuldeep, additional, Ramos, Emilio, additional, van Oosterhout, Matthijs F.M., additional, Olimpio, Eduardo P., additional, de Ligt, Joep, additional, Dijkstra, Krijn K., additional, Smit, Egbert F., additional, van der Linden, Maarten, additional, Voest, Emile E., additional, van Moorsel, Coline H.M., additional, van der Ent, Cornelis K., additional, Cuppen, Edwin, additional, van Oudenaarden, Alexander, additional, Coenjaerts, Frank E., additional, Meyaard, Linde, additional, Bont, Louis J., additional, Peters, Peter J., additional, Tans, Sander J., additional, van Zon, Jeroen S., additional, Boj, Sylvia F., additional, Vries, Robert G., additional, Beekman, Jeffrey M., additional, and Clevers, Hans, additional

Published
2018
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30. Disease Modeling in Stem Cell-Derived 3D Organoid Systems

Author

CMM Sectie Molecular Cancer Research, Cancer, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, Dutta, Devanjali, Heo, Inha, Clevers, Hans, CMM Sectie Molecular Cancer Research, Cancer, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, Dutta, Devanjali, Heo, Inha, and Clevers, Hans

Published
2017

31. Controlling the diversity of cell populations in a stem cell culture

Author

Heo, Inha, Clevers, Hans, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Abstract

Culturing intestinal stem cells into 3D organoids results in heterogeneous cell populations, reflecting the in vivo cell type diversity. In a recent paper published in Nature, Wang et al. established a culture condition for a highly homogeneous population of intestinal stem cells.

Published
2015

34. Expanding intestinal stem cells in culture

Author

CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Child Health, Heo, Inha, Clevers, Hans, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Child Health, Heo, Inha, and Clevers, Hans

Published
2015

37. Functional Repair of CFTR by CRISPR/Cas9 in Intestinal Stem Cell Organoids of Cystic Fibrosis Patients

Author

Schwank, Gerald, primary, Koo, Bon-Kyoung, additional, Sasselli, Valentina, additional, Dekkers, Johanna F., additional, Heo, Inha, additional, Demircan, Turan, additional, Sasaki, Nobuo, additional, Boymans, Sander, additional, Cuppen, Edwin, additional, van der Ent, Cornelis K., additional, Nieuwenhuis, Edward E.S., additional, Beekman, Jeffrey M., additional, and Clevers, Hans, additional

Published
2013
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42. Structural and Functional Insights into Dom34, a Key Component of No-Go mRNA Decay

Author

Lee, Hyung Ho, primary, Kim, Youn-Sung, additional, Kim, Kyoung Hoon, additional, Heo, Inha, additional, Kim, Sang Kyu, additional, Kim, Olesya, additional, Kim, Hye Kyung, additional, Yoon, Ji Young, additional, Kim, Hyoun Sook, additional, Kim, Do Jin, additional, Lee, Sang Jae, additional, Yoon, Hye Jin, additional, Kim, Soon Jong, additional, Lee, Byung Gil, additional, Song, Hyun Kyu, additional, Kim, V. Narry, additional, Park, Chung-Mo, additional, and Suh, Se Won, additional

Published
2007
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44. Dicer recognizes the 5? end of RNA for efficient and accurate processing.

Author

Jong-Eun Park, Heo, Inha, Yuan Tian, Simanshu, Dhirendra K., Hyeshik Chang, Jee, David, Patel, Dinshaw J., and Kim, V. Narry

Subjects
*RNA, *GENE silencing, *NUCLEOTIDES, *DOUBLE-stranded RNA, *EMBRYONIC stem cells, *PHOSPHATES
Abstract

A hallmark of RNA silencing is a class of approximately 22-nucleotide RNAs that are processed from double-stranded RNA precursors by Dicer. Accurate processing by Dicer is crucial for the functionality of microRNAs (miRNAs). The current model posits that Dicer selects cleavage sites by measuring a set distance from the 3? overhang of the double-stranded RNA terminus. Here we report that human Dicer anchors not only the 3? end but also the 5? end, with the cleavage site determined mainly by the distance (?22 nucleotides) from the 5? end (5? counting rule). This cleavage requires a 5?-terminal phosphate group. Further, we identify a novel basic motif (5? pocket) in human Dicer that recognizes the 5?-phosphorylated end. The 5? counting rule and the 5? anchoring residues are conserved in Drosophila Dicer-1, but not in Giardia Dicer. Mutations in the 5? pocket reduce processing efficiency and alter cleavage sites in vitro. Consistently, miRNA biogenesis is perturbed in vivo when Dicer-null embryonic stem cells are replenished with the 5?-pocket mutant. Thus, 5?-end recognition by Dicer is important for precise and effective biogenesis of miRNAs. Insights from this study should also afford practical benefits to the design of small hairpin RNAs. [ABSTRACT FROM AUTHOR]

Published
2011
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45. Intestinal organoid cocultures with microbes

Author

Puschhof, Jens, Pleguezuelos-Manzano, Cayetano, Martinez-Silgado, Adriana, Akkerman, Ninouk, Saftien, Aurelia, Boot, Charelle, de Waal, Amy, Beumer, Joep, Dutta, Devanjali, Heo, Inha, and Clevers, Hans

Subjects
stem-cells, expansion, host, responses, rna, in-vitro
Abstract

This protocol comprises various methods to coculture organoids (particularly human small intestinal and colon organoids) with microbes, including microinjection into the lumen and periphery of 3D organoids and exposure of organoids to microbes in a 2D layer., Adult-stem-cell-derived organoids model human epithelial tissues ex vivo, which enables the study of host-microbe interactions with great experimental control. This protocol comprises methods to coculture organoids with microbes, particularly focusing on human small intestinal and colon organoids exposed to individual bacterial species. Microinjection into the lumen and periphery of 3D organoids is discussed, as well as exposure of organoids to microbes in a 2D layer. We provide detailed protocols for characterizing the coculture with regard to bacterial and organoid cell viability and growth kinetics. Spatial relationships can be studied by fluorescence live microscopy, as well as scanning electron microscopy. Finally, we discuss considerations for assessing the impact of bacteria on gene expression and mutations through RNA and DNA sequencing. This protocol requires equipment for standard mammalian tissue culture, or bacterial or viral culture, as well as a microinjection device.

46. Identification of Z-Tyr-Ala-CHN 2 , a Cathepsin L Inhibitor with Broad-Spectrum Cell-Specific Activity against Coronaviruses, including SARS-CoV-2.

Author

Doijen J, Temmerman K, Van den Eynde C, Diels A, Van den Broeck N, Van Gool M, Heo I, Jaensch S, Zwaagstra M, Diosa Toro M, Chiu W, De Jonghe S, Leyssen P, Bojkova D, Ciesek S, Cinatl J, Verschueren L, Buyck C, Van Kuppeveld F, Neyts J, Van Loock M, and Van Damme E

Abstract

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control by vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of severe COVID-19. We report the discovery of a small molecule, Z-Tyr-Ala-CHN 2 , which was identified in a cell-based antiviral screen. The molecule exerts sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and human coronavirus 229E. Time-of-addition studies reveal that Z-Tyr-Ala-CHN 2 acts at the early phase of the infection cycle, which is in line with the observation that the molecule inhibits cathepsin L. This results in antiviral activity against SARS-CoV-2 in VeroE6, A549-hACE2, and HeLa-hACE2 cells, but not in Caco-2 cells or primary human nasal epithelial cells since the latter two cell types also permit entry via transmembrane protease serine subtype 2 (TMPRSS2). Given their cell-specific activity, cathepsin L inhibitors still need to prove their value in the clinic; nevertheless, the activity profile of Z-Tyr-Ala-CHN 2 makes it an interesting tool compound for studying the biology of coronavirus entry and replication.

Published
2023
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47. Studying Cryptosporidium Infection in 3D Tissue-derived Human Organoid Culture Systems by Microinjection.

Author

Dutta D, Heo I, and O'Connor R

Subjects
Humans, Intestines cytology, Intestines microbiology, Cryptosporidium parvum physiology, Microinjections, Organoids cytology, Tissue Culture Techniques methods
Abstract

Cryptosporidium parvum is one of the major causes of human diarrheal disease. To understand the pathology of the parasite and develop efficient drugs, an in vitro culture system that recapitulates the conditions in the host is needed. Organoids, which closely resemble the tissues of their origin, are ideal for studying host-parasite interactions. Organoids are three-dimensional (3D) tissue-derived structures which are derived from adult stem cells and grow in culture for extended periods of time without undergoing any genetic aberration or transformation. They have well defined polarity with both apical and basolateral surfaces. Organoids have various applications in drug testing, bio banking, and disease modeling and host-microbe interaction studies. Here we present a step-by-step protocol of how to prepare the oocysts and sporozoites of Cryptosporidium for infecting human intestinal and airway organoids. We then demonstrate how microinjection can be used to inject the microbes into the organoid lumen. There are three major methods by which organoids can be used for host-microbe interaction studies-microinjection, mechanical shearing and plating, and by making monolayers. Microinjection enables maintenance of the 3D structure and allows for precise control of parasite volumes and direct apical side contact for the microbes. We provide details for optimal growth of organoids for either imaging or oocyst production. Finally, we also demonstrate how the newly generated oocysts can be isolated from the organoid for further downstream processing and analysis.

Published
2019
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