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.
Current Members
Current Members
Mònica Díaz Ferrer
Research Assistant

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].