Jordi Guiu
@ku.dk
Copenhagen University
Scopus Publications
- Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition
Martti Maimets, Mikhail Nikolaev, Cecilia Lövkvist, Fabien Bertillot, Hjalte List Larsen, Raul Bardini Bressan, Antonios Georgantzoglou, Nikolce Gjorevski, Eirini Filidou, Maureen Zøylner, Stine Lind Hansen, Astrid M. Baattrup, Isidora Banjac, Jordi Guiu, Sara A. Wickström, Matthias P. Lutolf, Kim B. Jensen
Cell Stem Cell, 2026
During morphogenesis, the intestine undergoes significant structural remodeling, transitioning from a simple tube of immature epithelium into a complex crypt-villus architecture housing mature cell types. However, the relationship between these structural changes and epithelial maturation has remained enigmatic. Using engineered scaffolds that replicate crypt-like geometries, we establish a robust platform for guiding the morphogenesis and differentiation of fetal intestinal cells into mature engineered tissues that mimic their in vivo counterparts. Mechanistically, tissue maturation is driven by cell crowding, leading to reduced YAP1 activation. Modulating YAP signaling in both engineered tissues and the developing mouse intestine alters epithelial lineage specification. These findings uncover a geometry-dependent mechanism that links tissue architecture to cell fate transitions. Our work provides a platform for modeling aspects of intestinal development and offers insights for refining stem cell differentiation protocols and regenerative strategies for intestinal disorders. • Crypt-like geometry promotes maturation of fetal intestinal epithelial cells • Engineered tissues display multi-lineage differentiation and epithelial organization • Cell crowding reduces YAP1 activity to drive epithelial maturation • YAP activity modulates cell lineage specification in vivo Using engineered scaffolds mimicking intestinal crypts, Maimets et al. show that tissue geometry drives epithelial maturation by regulating YAP activity. Crypt-like structures promote differentiation of fetal cells, providing insight into how form guides function and offering a platform for modeling intestinal development and repair. - Reply
Ilias Moraitis, Jordi Guiu
Gastroenterology, 2025 - 3D bioprinting of human iPSC-derived cardiac constructs with microvascular network support for improved graft survival in vivo
Léa Pourchet, Laura Casado-Medina, Yvonne Richaud-Patin, Karine Tadevosyan, Alba Morillas-García, Edgar Lorenzo, Ioannis Lazis, Antoni Ventura, Jagoda Litowczenko, Jordi Guiu, Angel Raya
Biofabrication, 2025
Cardiac tissue engineering is a rapidly growing field that holds great promise for the development of new therapies for heart disease. While significant progress has been made in the field over the past two decades, engineering functional myocardium of clinically relevant size and thickness remains an unmet challenge. A major roadblock in this respect is the current difficulty in incorporating efficient vascularization into engineered constructs. One potential solution involves the use of microvascular fragments from adipose tissue, which have demonstrated encouraging results in improving vascularization and graft survival following transplantation. However, this method lacks precise control over the vascular architecture within the constructs. Here, we set out to investigate the use of 3D bioprinting for the fabrication of human cardiac tissue constructs composed of human induced pluripotent stem cell derivatives, while allowing for the precise control of the distribution and density of microvessel fragments within the bioprinted constructs. We carefully selected and optimized bioink compositions based on their printability, biocompatibility, and construct stability. Following transplantation into immunodeficient mice, 3D bioprinted cardiac constructs containing microvessel fragments exhibited rapid and efficient vascularization, resulting in prolonged graft survival. Overall, our studies underscore the advantages of employing engineering design and self-assembly across different scales to address current limitations of tissue engineering, and highlight the usefulness of 3D bioprinting in this context. - Mucosal Macrophages Govern Intestinal Regeneration in Response to Injury
Ilias Moraitis, Jasin Taelman, Borja Arozamena, Loris Mularoni, Olga Wienskowska, Xavier Sanjuan Garriga, Laura Arregui, Milica Stefanovic, Ignasi Modolell Farré, Ferran Guedea, Mònica Diaz, Jordi Guiu
Gastroenterology, 2025
BACKGROUND & AIMS Cancer patients treated with radiotherapy in the abdominal and pelvic cavity develop radiation-induced enteritis, a condition that impairs their quality of life. Radiation injury depletes proliferative intestinal stem cells (ISCs); in response to this, the epithelium activates a regenerative program that facilitates the healing of the intestine. However, the mechanisms that induce the activation of the intestinal regenerative program are poorly characterized. METHODS In this study, we induced radiation-induced enteritis in mice through abdominal irradiation, mimicking clinical scenarios. Through imaging and flow cytometric analysis, we investigated the recruitment of macrophages to the small intestine during injury and healing. Additionally, we developed a co-culture system for mouse and human intestinal organoids and macrophages to explore the crosstalk between these cells. Then combining in vivo ablation of macrophages, fluorescent lineage tracing, imaging, bulk RNA-sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), human intestinal organoids and cell trajectory analysis, we study at cellular and molecular level the macrophage induction of intestinal regeneration. RESULTS Our findings revealed that macrophages are recruited around the intestinal stem cell compartment upon radiation injury, promoting a fetal-like reprogramming and proliferation of epithelial cells that drives the regeneration process. In contrast macrophage ablation led to compromised regeneration. Moreover, our scRNA-seq analysis identified key secreted molecules, nrg1 and spp1, as pivotal players in regulating this process. Additionally, characterization of human macrophage/organoid co-cultures and cell trajectory inference confirmed the conservation of macrophages' role in triggering the regenerative program in primary human cells. CONCLUSIONS This study identifies macrophages as essential contributors to intestinal regeneration beyond their innate immune response. Targeting macrophages therapeutically may hold promise in enhancing regeneration and improving the quality of life for cancer survivors. - Enhanced small intestinal organoid-derived epithelial cell adhesion and growth in organ-on-a-chip devices
Federica Quacquarelli, Sergio Davila, Jasin Taelman, Jordi Guiu, Maria Antfolk
Rsc Advances, 2025
PDMS functionalization and adhesion protein coatings in combination with different medium formulations was assessed for the adhesion and growth of intestinal epithelial cells. - Gut microbiota controlling radiation-induced enteritis and intestinal regeneration
Ilias Moraitis, Jordi Guiu, Josep Rubert
Trends in Endocrinology and Metabolism, 2023
Cancer remains the second leading cause of mortality, with nearly 10 million deaths worldwide in 2020. In many cases, radiotherapy is used for its anticancer effects. However, radiation causes healthy tissue toxicity as a side effect. In intra-abdominal and pelvic malignancies, the healthy bowel is inevitably included in the radiation field, causing radiation-induced enteritis and dramatically affecting the gut microbiome. This condition is associated with significant morbidity and mortality that impairs cancer patients' and survivors' quality of life. This Review provides a critical overview of the main drivers in modulating the gut microenvironment in homeostasis, disease, and injury, focusing on gut microbial metabolites and microorganisms that influence epithelial regeneration upon radiation injury. - An organoid-based CRISPR-Cas9 screen for regulators of intestinal epithelial maturation and cell fate
Stine L. Hansen, Hjalte L. Larsen, Laura M. Pikkupeura, Grzegorz Maciag, Jordi Guiu, Iris Müller, Ditte L. Clement, Christina Mueller, Jens Vilstrup Johansen, Kristian Helin, Mads Lerdrup, Kim B. Jensen
Science Advances, 2023
Generation of functionally mature organs requires exquisite control of transcriptional programs governing cell state transitions during development. Despite advances in understanding the behavior of adult intestinal stem cells and their progeny, the transcriptional regulators that control the emergence of the mature intestinal phenotype remain largely unknown. Using mouse fetal and adult small intestinal organoids, we uncover transcriptional differences between the fetal and adult state and identify rare adult-like cells present in fetal organoids. This suggests that fetal organoids have an inherent potential to mature, which is locked by a regulatory program. By implementing a CRISPR-Cas9 screen targeting transcriptional regulators expressed in fetal organoids, we establish Smarca4 and Smarcc1 as important factors safeguarding the immature progenitor state. Our approach demonstrates the utility of organoid models in the identification of factors regulating cell fate and state transitions during tissue maturation and reveals that SMARCA4 and SMARCC1 prevent precocious differentiation during intestinal development. - Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation
Laura M. Pikkupeura, Raul B. Bressan, Jordi Guiu, Yun Chen, Martti Maimets, Daniela Mayer, Pawel J. Schweiger, Stine L. Hansen, Grzegorz J. Maciag, Hjalte L. Larsen, Kadi Lõhmussaar, Marianne Terndrup Pedersen, Joji M. Yap Teves, Jette Bornholdt, Vladimir Benes, Albin Sandelin, Kim B. Jensen
Science Advances, 2023
During intestinal organogenesis, equipotent epithelial progenitors mature into phenotypically distinct stem cells that are responsible for lifelong maintenance of the tissue. While the morphological changes associated with the transition are well characterized, the molecular mechanisms underpinning the maturation process are not fully understood. Here, we leverage intestinal organoid cultures to profile transcriptional, chromatin accessibility, DNA methylation, and three-dimensional (3D) chromatin conformation landscapes in fetal and adult epithelial cells. We observed prominent differences in gene expression and enhancer activity, which are accompanied by local changes in 3D organization, DNA accessibility, and methylation between the two cellular states. Using integrative analyses, we identified sustained Yes-Associated Protein (YAP) transcriptional activity as a major gatekeeper of the immature fetal state. We found the YAP-associated transcriptional network to be regulated at various levels of chromatin organization and likely to be coordinated by changes in extracellular matrix composition. Together, our work highlights the value of unbiased profiling of regulatory landscapes for the identification of key mechanisms underlying tissue maturation. - Mesenchymal-epithelial crosstalk shapes intestinal regionalisation via Wnt and Shh signalling
Martti Maimets, Marianne Terndrup Pedersen, Jordi Guiu, Jes Dreier, Malte Thodberg, Yasuko Antoku, Pawel J. Schweiger, Leonor Rib, Raul Bardini Bressan, Yi Miao, K. Christopher Garcia, Albin Sandelin, Palle Serup, Kim B. Jensen
Nature Communications, 2022
Organs are anatomically compartmentalised to cater for specialised functions. In the small intestine (SI), regionalisation enables sequential processing of food and nutrient absorption. While several studies indicate the critical importance of non-epithelial cells during development and homeostasis, the extent to which these cells contribute to regionalisation during morphogenesis remains unexplored. Here, we identify a mesenchymal-epithelial crosstalk that shapes the developing SI during late morphogenesis. We find that subepithelial mesenchymal cells are characterised by gradients of factors supporting Wnt signalling and stimulate epithelial growth in vitro. Such a gradient impacts epithelial gene expression and regional villus formation along the anterior-posterior axis of the SI. Notably, we further provide evidence that Wnt signalling directly regulates epithelial expression of Sonic Hedgehog (SHH), which, in turn, acts on mesenchymal cells to drive villi formation. Taken together our results uncover a mechanistic link between Wnt and Hedgehog signalling across different cellular compartments that is central for anterior-posterior regionalisation and correct formation of the SI. - Human Intestinal Organoids: Promise and Challenge
Jasin Taelman, Mònica Diaz, Jordi Guiu
Frontiers in Cell and Developmental Biology, 2022
The study of human intestinal biology in healthy and diseased conditions has always been challenging. Primary obstacles have included limited tissue accessibility, inadequate in vitro maintenance and ethical constrains. The development of three-dimensional organoid cultures has transformed this entirely. Intestinal organoids are self-organized three-dimensional structures that partially recapitulate the identity, cell heterogeneity and cell behaviour of the original tissue in vitro. This includes the capacity of stem cells to self-renew, as well as to differentiate towards major intestinal lineages. Therefore, over the past decade, the use of human organoid cultures has been instrumental to model human intestinal development, homeostasis, disease, and regeneration. Intestinal organoids can be derived from pluripotent stem cells (PSC) or from adult somatic intestinal stem cells (ISC). Both types of organoid sources harbour their respective strengths and weaknesses. In this mini review, we describe the applications of human intestinal organoids, discussing the differences, advantages, and disadvantages of PSC-derived and ISC-derived organoids. - In Vivo Studies Should Take Priority When Defining Mechanisms of Intestinal Crypt Morphogenesis
Jordi Guiu, Kim B. Jensen
Cellular and Molecular Gastroenterology and Hepatology, 2022 - Rebuttal to: Organoid vs Mouse Model: Which is a Better Research Tool to Understand the Biologic Mechanisms of Intestinal Epithelium?
Jordi Guiu, Kim B. Jensen
Cellular and Molecular Gastroenterology and Hepatology, 2022 - A Quantitative Lineage-Tracing Approach to Understand Morphogenesis in Gut
Svetlana Ulyanchenko, Jordi Guiu
Methods in Molecular Biology, 2021 - Tracing the origin of adult intestinal stem cells
Jordi Guiu, Edouard Hannezo, Shiro Yui, Samuel Demharter, Svetlana Ulyanchenko, Martti Maimets, Anne Jørgensen, Signe Perlman, Lene Lundvall, Linn Salto Mamsen, Agnete Larsen, Rasmus H. Olesen, Claus Yding Andersen, Lea Langhoff Thuesen, Kristine Juul Hare, Tune H. Pers, Konstantin Khodosevich, Benjamin D. Simons, Kim B. Jensen
Nature, 2019 - YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration
Shiro Yui, Luca Azzolin, Martti Maimets, Marianne Terndrup Pedersen, Robert P. Fordham, Stine L. Hansen, Hjalte L. Larsen, Jordi Guiu, Mariana R.P. Alves, Carsten F. Rundsten, Jens V. Johansen, Yuan Li, Chris D. Madsen, Tetsuya Nakamura, Mamoru Watanabe, Ole H. Nielsen, Pawel J. Schweiger, Stefano Piccolo, Kim B. Jensen
Cell Stem Cell, 2018 - Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia
Daniel Perea, Jordi Guiu, Bruno Hudry, Chrysoula Konstantinidou, Alexandra Milona, Dafni Hadjieconomou, Thomas Carroll, Nina Hoyer, Dipa Natarajan, Jukka Kallijärvi, James A Walker, Peter Soba, Nikhil Thapar, Alan J Burns, Kim B Jensen, Irene Miguel‐Aliaga
EMBO Journal, 2017 - Notch signal strength controls cell fate in the haemogenic endothelium
Leonor Gama-Norton, Eva Ferrando, Cristina Ruiz-Herguido, Zhenyi Liu, Jordi Guiu, Abul B. M. M. K. Islam, Sung-Uk Lee, Minhong Yan, Cynthia J. Guidos, Nuria López-Bigas, Takahiro Maeda, Lluis Espinosa, Raphael Kopan, Anna Bigas
Nature Communications, 2015 - From Definitive Endoderm to Gut - A Process of Growth and Maturation
Jordi Guiu, Kim B. Jensen
Stem Cells and Development, 2015 - Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch
E. Lopez-Arribillaga, V. Rodilla, L. Pellegrinet, J. Guiu, M. Iglesias, A. C. Roman, S. Gutarra, S. Gonzalez, P. Munoz-Canoves, P. Fernandez-Salguero, F. Radtke, A. Bigas, L. Espinosa
Development Cambridge, 2015 - Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium
Il Ho Jang, Yi-Fen Lu, Long Zhao, Pamela L. Wenzel, Tsutomu Kume, Sumon M. Datta, Natasha Arora, Jordi Guiu, Mounia Lagha, Peter G. Kim, Eun Kyoung Do, Jae Ho Kim, Thorsten M. Schlaeger, Leonard I. Zon, Anna Bigas, Caroline E. Burns, George Q. Daley
Blood, 2015 - Identification of Cdca7 as a novel Notch transcriptional target involved in hematopoietic stem cell emergence
Jordi Guiu, Dylan J.M. Bergen, Emma De Pater, Abul B.M.M.K. Islam, Verónica Ayllón, Leonor Gama-Norton, Cristina Ruiz-Herguido, Jessica González, Nuria López-Bigas, Pablo Menendez, Elaine Dzierzak, Lluis Espinosa, Anna Bigas
Journal of Experimental Medicine, 2014 - Notch and Wnt signaling in the emergence of hematopoietic stem cells
Anna Bigas, Jordi Guiu, Leonor Gama-Norton
Blood Cells Molecules and Diseases, 2013 - Hes repressors are essential regulators of hematopoietic stem cell development downstream of notch signaling
Jordi Guiu, Ritsuko Shimizu, Teresa D’Altri, Stuart T. Fraser, Jun Hatakeyama, Emery H. Bresnick, Ryoichiro Kageyama, Elaine Dzierzak, Masayuki Yamamoto, Lluis Espinosa, Anna Bigas
Journal of Experimental Medicine, 2013 - Hematopoietic stem cell development requires transient Wnt/β-catenin activity
Cristina Ruiz-Herguido, Jordi Guiu, Teresa D'Altri, Julia Inglés-Esteve, Elaine Dzierzak, Lluis Espinosa, Anna Bigas
Journal of Experimental Medicine, 2012 - The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia
Lluis Espinosa, Severine Cathelin, Teresa D'Altri, Thomas Trimarchi, Alexander Statnikov, Jordi Guiu, Veronica Rodilla, Julia Inglés-Esteve, Josep Nomdedeu, Beatriz Bellosillo, Carles Besses, Omar Abdel-Wahab, Nicole Kucine, Shao-Cong Sun, Guangchan Song, Charles C. Mullighan, Ross L. Levine, Klaus Rajewsky, Iannis Aifantis, Anna Bigas
Cancer Cell, 2010 - Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1
Àlex Robert-Moreno, Jordi Guiu, Cristina Ruiz-Herguido, M Eugenia López, Julia Inglés-Esteve, Lluis Riera, Alex Tipping, Tariq Enver, Elaine Dzierzak, Thomas Gridley, Lluis Espinosa, Anna Bigas
EMBO Journal, 2008
