Research group/lab

Laboratory of Experimental Transplantation and Intestinal Surgery (LETIS)

The Laboratory of Experimental Transplantation and Intestinal Surgery (LETIS) is part of the Department of Surgery and works in close collaboration with the Department of Gastroenterology & Hepatology. We have a strong focus on translational research in the field of regenerative medicine, organ transplantation, liver disease and liver cancer. The research aims to provide basic and applied knowledge using organoids, bio-scaffolds, animal models, and organ perfusion technologies.

Transplant Institute

About our research group/lab

Our research

Organoid technology

We use 3D cell cultures of liver and extahepatic bile duct tissue to grow organoids. These can be used to study liver regeneration and tissue engineering, and to model liver diseases, including primary liver cancer.

Liver disease modeling

Organoids grown from patient liver, bile ducts and bile retain the patient characteristics which makes these cultures very useful to study the disease and their response to therapy/medicine in more detail. We have made disease models for Primary Sclerosing Cholangitis (PSC), Alagille Syndrome, Alpha-1 Anti-Trypsine Deficiency, cholangiocarcinoma, and several more.

Tissue engineering
To overcome the donor organ shortage, we use native liver and bile duct extracellular matrix (ECM) as a basis for tissue engineering. The ECM is provided by decellularization (removal of all cells) of whole human livers that are unsuited for transplantation. These so-called scaffolds can then be recolonized using organoids and stromal cells to engineer functional liver and bile duct tissue, which can be used for regenerative-oriented research but, in the long term for transplantation.

Machine perfusion

In close collaboration with the clinicians/surgeons in our department, we study the use of machine perfusion to assess the quality of graft livers and kidneys and even improve the quality if needed. For this, we are aiming to find biomarkers that can be analyzed fast and reliably to assess graft quality and develop new procedures, including cell therapy or drug administration “on the pump”.

Aging patients

The average life expectancy in the last century has increased from approximately 50 to over 80 years. Concurrent with this rise there has been an increase in the number of people with pathologies such as organ failure and cancer. In addition, older people are more vulnerable to adverse side effects of medical and surgical treatment.

We study interventions that improve resistance to these adverse side effects. These include short-term caloric restriction, that improves resistance to these adverse effects, and novel senolytic therapies, that are able to rejuvenate old organs, and perhaps even people.

Studies performed focus on 3 major themes:

-Ischemia–reperfusion injury as serious complication after organ transplantation of old and suboptimal donor organs.

-Loss of muscle mass in aging individuals and cancer patients

-Surgical treatment of morbid obesity.
Within these themes, we aim to develop innovative preventative or therapeutic interventions. A fruitful collaboration with surgical and medical clinics and a strong focus on translational research has facilitated the translation of our data generated in the lab into clinical protocols. These include the optimization of clinical dietary restriction protocols in transplantation-, and bariatric surgery as well as inflammatory bowel disease and chemotherapy treatment.

Key Publications

Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids.

Marsee A, Roos FJM, Verstegen MMA; HPB Organoid Consortium, Gehart H, de Koning E, Lemaigre F, Forbes SJ, Peng WC, Huch M, Takebe T, Vallier L, Clevers H, Spee B/van der Laan LJW Cell Stem Cell. 2021 May 6;28(5):816-832

Bile Duct Repair in Human Liver Grafts: Effective Cholangiocyte Organoid Engraftment and Plasticity.

van der Laan LJW, Roos FJM, Verstegen MMA. Hepatology. 2021 May 2. doi: 10.1002/hep.31877.

Human Bile Contains Cholangiocyte Organoid-Initiating Cells Which Expand as Functional Cholangiocytes in Non-canonical Wnt Stimulating Conditions.

Roos FJM, Verstegen MMA, Muñoz Albarinos L, Roest HP, Poley JW, Tetteroo GWM, IJzermans JNM, van der Laan LJW. Front Cell Dev Biol. 2021 Feb 9;8:630492.

Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease.

Verstegen MMA, Roos FJM, Burka K, Gehart H, Jager M, de Wolf M, Bijvelds MJC, de Jonge HR, Ardisasmita AI, van Huizen NA, Roest HP, de Jonge J, Koch M, Pampaloni F, Fuchs SA, Schene IF, Luider TM, van der Doef HPJ, Bodewes FAJA, de Kleine RHJ, Spee B, Kremers GJ, Clevers H, IJzermans JNM, Cuppen E, van der Laan LJW. Sci Rep. 2020 Dec 14;10(1):21900.

First Report on Ex Vivo Delivery of Paracrine Active Human Mesenchymal Stromal Cells to Liver Grafts During Machine Perfusion.

Verstegen MMA, Mezzanotte L, Ridwan RY, Wang K, de Haan J, Schurink IJ, Sierra Parraga JM, Hoogduijn M, Kessler BM, Huang H, Hall SRR, IJzermans JNM, Löwik CWGM, van der Laan LJW, de Jonge J. Transplantation. 2020 Jan;104(1):e5-e7.

Effects of Protein and Calorie Restriction on the Metabolism and Toxicity Profile of Irinotecan in Cancer Patients.

de Man FM, van Eerden RAG, van Doorn GM, Oomen-de Hoop E, Koolen SLW, Olieman JF, de Bruijn P, Veraart JN, van Halteren HK, Sandberg Y, Moelker A, IJzermans JNM, Lolkema MP, van Gelder T, Dollé MET, de Bruin RWF, Mathijssen RHJ. Clin Pharmacol Ther. 2021; May: 109(5): 1304-1313

Pre-Operative Fasting Provides Long Term Protection Against Chronic Renal Damage Induced by Ischaemia Reperfusion Injury in Wild Type and Aneurysm Prone Fibulin-4 Mice.

Saat TC, van der Pluijm I, Ridwan Y, van Damme-van den Engel S, van Heijningen PM, Clahsen-van Groningen MC, Verhagen HJM, IJzermans JNM, Essers J, de Bruin RWF. Eur J Vasc Endovasc Surg. 2020 Dec;60(6):905-915.

Protein and calorie restriction may improve outcomes in living kidney donors and kidney transplant recipients.

Jongbloed F, de Bruin RWF, Steeg HV, Beekhof P, Wackers P, Hesselink DA, Hoeijmakers JHJ, Dollé MET, IJzermans JNM. Aging (Albany NY). 2020 Jul 11;12(13):12441-12467.

The transcriptomic response to irinotecan in colon carcinoma bearing mice preconditioned by fasting.

Jongbloed F, Huisman SA, van Steeg H, Pennings JLA, IJzermans JNM, Dollé MET, de Bruin RWF Oncotarget. 2019 Mar 15;10(22):2224-2234.

Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting.

Levolger S, Wiemer EAC, van Vugt JLA, Huisman SA, van Vledder MG, van Damme-van Engel S, Ambagtsheer G, IJzermans JNM, de Bruin RWF. Sci Rep. 2019; 8;9(1):9826

All publications of LETIS on PUBMED