Regenerative Medicine Utrecht

Sabine Middendorp, PhD

Associate professor
Pediatric Gastroenterology
UMC-WKZ
s.middendorp@umcutrecht.nl

Pediatric Gastroenterology.

Dr. Sabine Middendorp received her PhD cum laude in May 2004 at the Erasmus MC Rotterdam. After a postdoc at the Netherlands Cancer Institute in Amsterdam, she started working with intestinal organoids in 2010, when she joined the lab of Edward Nieuwenhuis at the Wilhelmina Children’s hospital (WKZ). In 2014 she received a personal NWO-VIDI and NWO-Aspasia grant and in 2015 she was appointed Associate Professor at the department of Pediatric Gastroenterology
of the UMC Utrecht-WKZ.

Currently, her work focuses on the use of patient-specific intestinal organoids for diagnostic purposes and to elucidate pathophysiology of disease. By performing functional studies in organoids, the lab tries to test and develop personalized medicine for individual patients.

Research

We collect biopsies from patients with intestinal disease, such as congenital chronic diarrhea. We then generate organoids (stem cell-based cultures) from these patients in the lab, which provide unique in vitro model systems to study the pathophysiology of these diseases.

One such life-threatening congenital disease is microvillus inclusion disease (MVID), which causes persistent watery diarrhea in the first week of life and is characterized by enterocyte abnormalities and malabsorption of nutrients. Current therapy strategies for MVID are not long lasting. Patients require life-long intravenous nutrition administration, which often leads to liver failure and clogging of veins ultimately leading to the need for intestinal transplantation. Although MVID is a very rare and recessive disease, the consequences are devastating and clearly there is an urgent need for new therapeutic interventions.

MVID is known to be caused by mutations in myosin Vb (MYO5B), encoding a motor protein that is implicated in organization of intracellular transport and cell surface polarity in epithelial cells. Recently, we have discovered a new causal gene for MVID, syntaxin 3 (STX3). STX3 is involved in membrane expression of proteins. The exact role of syntaxin 3 and myosin Vb in the MVID disease mechanism has not yet been resolved. We study the defects in enterocytes from MVID patients and test potential therapies to correct these defects. Next to MVID we also study other intestinal diseases, such as fat intolerance and chronic diarrhea.

Selected literature

Pubmed search: Middendorp S

  1. Van Rijn J.M.*, K. Schneeberger*, C.L. Wiegerinck, E.E.S. Nieuwenhuis and S. Middendorp. Novel approaches: Tissue engineering and stem cells – in vitro modelling of the gut. Best Practice & Research Clinical Gastroenterology 2016 (30) 281. *Equal contribution.
  2. Schneeberger K, G.F. Vogel, H. Teunissen, D.D. van Ommen, H. Begthel, L. El Bouazzaoui, A.H. van Vugt, J.M. Beekman, J. Klumperman, T. Müller, A. Janecke, P. Gerner, L.A. Huber, M.W. Hess, H. Clevers, J.H. van Es, E.E.S. Nieuwenhuis and S. Middendorp. An inducible mouse model for microvillus inclusion disease reveal a role for myosin Vb in apical and basolateral trafficking. Proc Natl Acad Sci USA 2015 (112) 12408.
  3. Wiegerinck C.L.*, A.R. Janecke*, K. Schneeberger*, G.F. Vogel*, D.Y. van Haaften-Visser*, J.C. Escher, R. Adam, C.E. Thöni, K. Pfaller, A.J. Jordan, C-A. Weis, I.J. Nijman, G.R. Monroe, P.M. van Hasselt, E. Cutz, J. Klumperman, H. Clevers, E.E.S. Nieuwenhuis, R.H.J. Houwen, G. van Haaften, M.W. Hess#, L.A. Huber#, J.M. Stapelbroek#, T. Müller# and S. Middendorp#. Loss of syntaxin 3 causes variant microvillus inclusion disease. Gastroenterology 2014 (147) 65. *,#Equal contribution.
  4. Middendorp S., K. Schneeberger*, C.L. Wiegerinck*, M. Mokry, R.D.L. Akkerman, S. van Wijngaarden, H. Clevers and E.E.S. Nieuwenhuis. Adult stem cells in the small intestine are intrinsically programmed with their location-specific function. Stem Cells 2014 (32) 1083. *Equal contribution.
  5. Dekkers J.F., C.L. Wiegerinck, H.R. de Jonge, I. Bronsveld, H.M. Janssens, K.M de Winter-de Groot, N.W.M. de Jong, M.J.C. Bijvelds, B.J. Scholte, E.E.S Nieuwenhuis, S. van den Brink, H. Clevers, C.K. van der Ent, S. Middendorp and J.M. Beekman. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med 2013 (19) Pages:939.

Contact

Sabine Middendorp, PhD
Regenerative Medicine Center, UMC Utrecht
s.middendorp@umcutrecht.nl
+31.618066833

Mailing address for correspondence and packages
Regenerative Medicine Center, UMC Utrecht
Uppsalalaan 8
3584 CT Utrecht
The Netherlands