Guiu Group

Cell Plasticity And Regeneration

Understanding the process of intestinal regeneration in order to develop treatments for cancer survivors

We aim to improve quality of life for cancer survivors, which suffer side effects of radiotherapy including an acute and chronic inflammation of the intestine. In order to achieve this goal, we study the cellular and molecular mechanisms involved in epithelial recovery after radiation injury. Furthermore we study the establishment of the chronic radiation-induced enteritis with a particular attention to the epithelial-immune cell crosstalk.
Jordi Guiu
Group Leader, Regenerative Medicine Program of IDIBELL
Group Leader of P-CMRC

Lab focus: Reeducating cells to cure disease; understanding cell plasticity to boost regeneration

The primary function of the intestine is the digestion and absorption of nutrients. The small intestine is composed of proliferative crypts and differentiated villus structures. The adult intestine is lined with epithelium, which is maintained by intestinal stem cells. Radiation therapy is a common treatment used in at least 50% of cancer patients and despite its efficiency in eradicating cancer it induces intestinal toxicity. Radiation triggers apoptosis of proliferative cells, this denudes the intestinal mucosa and in turn results in an inflammatory response; the main features are initially an acute atrophy of the mucosa and at later stages fibrosis of the intestinal wall. The number of cancer survivors with post-radiation dysfunction of intestinal epithelium is continuously rising. However this condition to date has no effective treatments. Our primary goal is to understand the mechanisms triggering these processes in order to develop therapeutic. Recent studies have illustrated that committed following injury have the ability to dedifferentiate and reacquire stem cell potential thus exhibiting previously unappreciated cell plasticity. This condition facilitates a quick and effective regenerative response. The roles of immune cells in this process, which are the cells responsible for triggering the inflammation, remain poorly characterized. We believe that unraveling the mechanisms that govern the ability to transition reversibly between cellular states will impact our understanding of tissue homeostasis and empower us with new and exciting opportunities to enhance intestinal regeneration.
Using state of the art technologies and a plethora of groundbreaking approaches such as patient derived intestinal organoids, complemented by mouse models, lineage tracing, single cell transcriptomics and 3-dimensional imaging we are unraveling the mechanisms that govern the ability to transition reversibly between cellular states. Furthermore, we are characterizing at the cellular and molecular levels the process of mucosa and submucosa injury upon irradiation in order to develop treatments to boost regeneration and reeducate cells to cure fibrosis.

Why it matters

The number of cancer survivors has drastically increased due to decades of research successes. As a consequence, cohorts of patients suffering unintended side effects of cancer therapies have rapidly increased. Cancer patients treated with radiation (radiotherapy) in the abdomen develop radiation-induced enteritis and suffer from bleeding and malabsorption due to mucosa ulceration; moreover half of those patients subsequently develop chronic enteritis characterized by intestinal fibrosis that may eventually lead to intestinal perforation and death in some cases. Current treatments for these pathologies are exclusively symptomatic because there is no medical cure. Therefore, it is imperative to provide mechanistic insights into radiation-induced enteritis in order to develop therapies that directly target and eventually cure these diseases.

Keywords

Regenerative medicine, Radiation induced-enteritis, radiotherapy side effects, intestine, epithelial regeneration, intestinal regeneration, intestinal stem cells, cellular plasticity, lineage tracing, organoids, transcriptomics

Publications

Guiu J, Hannezo E, Yui S, Demharter S, Ulyanchenko S, Maimets M, Jorgensen A, Perlman S, Lundvall L, Mamsen LS, Larsen A, Olesen RH, Andersen CY, Thuesen LL, Hare KJ, Pers TH, Khodosevich K, Simons BD, Jensen KB (2019) Tracing the origin of adult intestinal stem cells. Nature. Nature Publishing Group. 570-7759, pp.107-111. ISSN 00280836.
Yui S, Azzolin L, Maimets M, Pedersen MT, Fordham RP, Hansen SL, Larsen HL, Guiu J, Alves MRP, Rundsten CF, Johansen JV, Li Y, Madsen CD, Nakamura T, Watanabe M, Nielsen OH, Schweiger PJ, Piccolo S, Jensen KB (2018) YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration. Cell Stem Cell. Cell Press. 22-1, pp.35-49.e7. ISSN 19345909.
Perea D, Guiu J, Hudry B, Konstantinidou C, Milona A, Hadjieconomou D, Carroll T, Hoyer N, Natarajan D, Kallijarvi J, Walker JA, Soba P, Thapar N, Burns AJ, Jensen KB, Miguel-Aliaga I (2017) Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia. EMBO Journal. Wiley-VCH Verlag. 36-20, pp.3029-3045. ISSN 02614189. (IF 2017: 10,55)
Guiu J, Jensen KB (2015) From Definitive Endoderm to Gut-a Process of Growth and Maturation. Stem Cells and Development. Mary Ann Liebert Inc.. 24-17, pp.1972-1983. ISSN 15473287.
Lopez-Arribillaga E, Rodilla V, Pellegrinet L, Guiu J, Iglesias M, Roman AC, Gutarra S, Gonzalez S, Munoz-Canoves P, Fernandez-Salguero P, Radtke F, Bigas A, Espinosa L (2015) Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch. Development (Cambridge). Company of Biologists Ltd. 142-1, pp.41-50. ISSN 09501991.
Gama-Norton L, Ferrando E, Ruiz-Herguido C, Liu Z, Guiu J, Islam AB, Lee SU, Yan M, Guidos CJ, Lopez-Bigas N, Maeda T, Espinosa L, Kopan R, Bigas A (2015) Notch signal strength controls cell fate in the haemogenic endothelium. Nature Communications. Nature Publishing Group. 6. ISSN 20411723.
Jang IH, Lu YF, Zhao L, Wenzel PL, Kume T, Datta SM, Arora N, Guiu J, Lagha M, Kim PG, Do EK, Kim JH, Schlaeger TM, Zon LI, Bigas A, Burns CE, Daley GQ (2015) Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium. Blood. American Society of Hematology. 125-9, pp.1418-1426. ISSN 00064971.
Guiu J, Bergen DJ, De Pater E, Islam AB, Ayllon V, Gama-Norton L, Ruiz-Herguido C, Gonzalez J, Lopez-Bigas N, Menendez P, Dzierzak E, Espinosa L, Bigas A (2014) Identification of Cdca7 as a novel Notch transcriptional target involved in hematopoietic stem cell emergence. Journal of Experimental Medicine. Rockefeller University Press. 211-12, pp.2411-2423. ISSN 00221007.
Guiu J, Shimizu R, D’Altri T, Fraser ST, Hatakeyama J, Bresnick EH, Kageyama R, Dzierzak E, Yamamoto M, Espinosa L, Bigas A (2013) Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling. Journal of Experimental Medicine. 210-1, pp.71-84. ISSN 00221007.
Bigas A, Guiu J, Gama-Norton L (2013) Notch and Wnt signaling in the emergence of hematopoietic stem cells. Blood Cells, Molecules, and Diseases. 51-4, pp.264-270. ISSN 10799796.
Ruiz-Herguido C, Guiu J, D’Altri T, Ingles-Esteve J, Dzierzak E, Espinosa L, Bigas A (2012) Hematopoietic stem cell development requires transient Wnt/beta-catenin activity. Journal of Experimental Medicine. 209-8, pp.1457-1468. ISSN 00221007.
Espinosa L, Cathelin S, D’Altri T, Trimarchi T, Statnikov A, Guiu J, Rodilla V, Ingles-Esteve J, Nomdedeu J, Bellosillo B, Besses C, Abdel-Wahab O, Kucine N, Sun SC, Song G, Mullighan CC, Levine RL, Rajewsky K, Aifantis I, Bigas A (2010) The Notch/Hes1 pathway sustains NF-kappaB activation through CYLD repression in T cell leukemia. Cancer Cell. Cell Press. 18-3, pp.268-281. ISSN 15356108.
Robert-Moreno A*, Guiu J*, Ruiz-Herguido C, Lopez ME, Ingles-Esteve J, Riera L, Tipping A, Enver T, Dzierzak E, Gridley T, Espinosa L, Bigas A (2008) Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1. EMBO Journal. 27-13, pp.1886-1895. ISSN 02614189. *Equal contribution to this work.
Ulyanchenko, S. & Guiu, J. A Quantitative Lineage-Tracing Approach to Understand Morphogenesis in Gut. Methods Mol Biol 2258, 29-40, doi:10.1007/978-1-0716-1174-6_3 (2021).
Current Members
Current Members
Mònica Díaz Ferrer
Research Assistant
Borja Arozamena
Lab Member
Ilias Moraitis
Lab Member
Jasin Taelman
Postdoctoral Researcher

Jordi Guiu
Group Leader, Regenerative Medicine Program of IDIBELL
Group Leader of P-CMRC

jguiu@idibell.cat

Dr Jordi Guiu studied BS in Biology (2006), Biochemistry (2007) and a Master of Science in Molecular Biotechnology (2008). Then he did a PhD in Biomedicine (2012) from Pompeu Fabra University to study the genetic circuitry that controls the establishment of hematopoietic stem cells. Subsequently he joined Dr. Kim B. Jensen lab (Copenhagen University) as a postdoc, were he obtained a Marie Curie fellowship (2014-2019). His postdoctoral work focused on the specification of intestinal stem cells during development using fate mapping technologies, state of the art imaging, biophysical modeling and a plethora of sequencing techniques. In 2019 Dr. Guiu was appointed Assistant Professor in Copenhagen University. In September 2019, he joined the P-CMRC/IDIBELL as independent group leader.

Dr Guiu pursue a research program aimed at improving quality of life for cancer survivors, which suffer side effects of radiotherapy including acute and chronic inflammation of the intestine known as radiation-induced enteritis.

Mònica Díaz Ferrer
Research Assistant
mdiaz@idibell.cat

Mònica Díaz holds a bachelor degree in Biochemistry and a PhD in Physiology from the University of Barcelona. During the PhD she studied the role of insulin regulating the glucose transport in skeletal muscle under the supervision of Dr Josep Planas. After finishing her PhD she stayed at the same laboratory as a postdoctoral researcher and assistant professor for one year.

In 2008, she did a short stay as postdoctoral researcher in CIBBIM-Nanomedicine at the Vall d’Hebron Research Institute, in the laboratory of Dr Julián Cerón that was focused on the modeling of human diseases in C. elegans.

Then she moved to Omnia Molecular, a biotech company devoted to the design and development of new anti-infectives targeted at difficult-to-treat infections, as a project manager. She was involved in the setup and development of a proprietary technology platform. Among her tasks, she was in charge of the cell-based assays, in particular their design and miniaturization to be incorporated into a high-throughput screening campaign.

In 2013, she joined the CMR[B] as a research assistant. Here, she has been involved in several projects aimed to model in vitro different diseases through the generation of patient-derived pluripotent stem cells.

Since September 2020, she works as a research assistant in the Cell plasticity and Regeneration group at P-CMR[C].

Borja Arozamena Villarrubia
Lab Member, Guiu Group
barozamena@idibell.cat

Borja Arozamena is a master’s student who has joined to the group of Cell Plasticity and Regeneration of the IDIBELL’s Program of Regenerative Medicine. Borja studied biotechnology at the University of Oviedo where he worked in his final project with novel treatments for the breast cancer at Maria Luisa Fernández’s laboratory at Oviedo’s university. Currently, he is coursing the master in Biomedical Research at Pompeu Fabra University and is working in his master thesis based on the intestinal regeneration mechanisms after radiation therapy. He entered the investigation world to explore his passion for research and his interest focuses on understanding the mechanisms behind cell regeneration. His next step is to get a PhD and continue working in science research.

Ilias Moraitis
Lab Member, Guiu Group
imoraitis@idibell.cat

Ilias obtained his Integrated Master’s degree (2019) in Biological Applications & Technology from the University of Ioannina, Greece. His master thesis was focused on the investigation of the influence of ETS2 repressor factor (ERF) on maturation and differentiation of thymocytes using mice as an animal model under the direction of Dr. George Thyphronitis.

After finishing his master’s degree, he spent six months as an ERASMUS internship fellow working in the Department of Experimental and Health Sciences at the laboratory of Human Natural Killer Cell Biology of University Pompeu Fabra Barcelona under the supervision of Dr. Miguel López-Botet and Dr. Elisenda Alari. His research was focused on the Characterization of a novel facet of the antibody-dependent NK cell response to Epstein-Barr virus.

Currently, Ilias is working on his Ph.D. project focused on understanding the process of intestinal regeneration in order to develop treatments for cancer survivors using mice as an animal model, under the direction of Dr. Jordi Guiu at the Regenerative Medicine Program of IDIBELL.

Jasin Taelman
Postdoctoral Researcher
jtaelman@idibell.cat

I obtained my Master’s in Biochemistry at Ghent University, Belgium, where I completed my master thesis on Epithelial-to-mesenchymal transition during the development of melanoma skin cancer. This experience developed my interest in stem cell maintenance and differentiation. I started my PhD on the transcriptomic analysis of human embryonic stem cell derivation, pluripotency maintenance and differentiation, with a focus on Wnt signaling at the University Hospital in Ghent. Stem cell research introduced me to germ cell precursor stem cells and I continued my research as a postdoctoral researcher at the Leiden University Medical Center, in the department of Anatomy and Embryology in Leiden, the Netherlands. There I worked on in vitro differentiation of stem cells towards germ cells and in vitro maturation of human gonad tissues. Throughout my PhD and postdoc I applied single cell RNA sequencing techniques, using both SMART-Seq and 10X Genomics approaches, to analyze gene expression differences between different cell populations, in the coding environment R. Currently, I am interested in applying single cell transcriptomic analysis on intestinal organoids in different treatment conditions, in the context of enteritis after irradiation treatment for cancer. For this I will work with Dr. Guiu in the Cell Plasticity and Regeneration group at Idibell, where we aim to elucidate dedifferentiation mechanisms and signaling pathways of adult human intestinal cell types transitioning towards a stem cell state, in order to better regulate regeneration of intestinal tissues.