Pre-clinical protein screening in bioengineered intestinal tubules
Jochemsen, P. ; Garssen, Johan ; Rietveld, P. ; Ariens, R.M.C. ; Bastiaan-Net, S. ; Wichers, H.J. ; Bergenhenegouwen, Jeroen van; Masereeuw, Rosalinde - \ 2019
- 1 p.
Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion
Jansen, Jitske ; Jansen, Katja ; Neven, Ellen ; Poesen, Ruben ; Othman, Amr ; Mil, Alain van; Sluijter, Joost ; Torano, Javier Sastre ; Zaal, Esther A. ; Berkers, Celia R. ; Esser, Diederik ; Wichers, Harry J. ; Ede, Karin van; Duursen, Majorie van; Burtey, Stéphane ; Verhaar, Marianne C. ; Meijers, Björn ; Masereeuw, Rosalinde - \ 2019
Proceedings of the National Academy of Sciences of the United States of America 116 (2019)32. - ISSN 0027-8424 - p. 16105 - 16110.
Indoxyl sulfate - Kidney proximal tubule - Organic anion transporter 1 - Remote sensing and signaling
Membrane transporters and receptors are responsible for balancing nutrient and metabolite levels to aid body homeostasis. Here, we report that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, metabolite levels through EGF receptors and downstream signaling to induce their secretion by up-regulating the organic anion transporter-1 (OAT1). Remote metabolite sensing and signaling was observed in kidneys from healthy volunteers and rats in vivo, leading to induced OAT1 expression and increased removal of indoxyl sulfate, a prototypical microbiome-derived metabolite and uremic toxin. Using 2D and 3D human proximal tubule cell models, we show that indoxyl sulfate induces OAT1 via AhR and EGFR signaling, controlled by miR-223. Concomitantly produced reactive oxygen species (ROS) control OAT1 activity and are balanced by the glutathione pathway, as confirmed by cellular metabolomic profiling. Collectively, we demonstrate remote metabolite sensing and signaling as an effective OAT1 regulation mechanism to maintain plasma metabolite levels by controlling their secretion.
Development and validation of bioengineered intestinal tubules for translational research aimed at safety and efficacy testing of drugs and nutrients
Jochems, Paulus G.M. ; Bergenhenegouwen, Jeroen van; Genderen, Anne Metje van; Eis, Sophie T. ; Wilod Versprille, Livia J.F. ; Wichers, Harry J. ; Jeurink, Prescilla V. ; Garssen, Johan ; Masereeuw, Rosalinde - \ 2019
Toxicology in Vitro 60 (2019). - ISSN 0887-2333 - p. 1 - 11.
Caco-2 - In vitro - Microfluidic and screening - Small intestine
Currently used intestinal cell models have limited translational value, therefore, development of novel in vitro intestinal models that recapitulate the human in vivo setting more closely are of interest. Here, an advanced intestinal model was developed by the incorporation of physiological parameters, such as extracellular matrix (ECM)elements and shear stress, to cultured Caco-2 cells in a 3-dimensional environment. Caco-2 cells grown on ECM-coated hollow fiber membranes (HFM)under physiological shear stress show an improved phenotype, as demonstrated by the presence of enterocytes, goblet, Paneth, enteroendocrine and stem cells. Additionally, this model showed signs of an improved morphology due to the appearance of villi-like structures. Similar to epithelial cells grown on Transwells™, the current model remains easy to use, cost efficient and allows apical and basolateral access. The bioengineered intestinal tubule was validated by exposure to Clostridium difficile toxin A, the leading cause of healthcare-associated diarrhea. The loss of the tight junction network was supported by an increase in inulin-FITC leakage and the number of goblet cells increased, in agreement with clinical findings. In addition to toxicity screening, the bioengineered intestinal tubules are considered useful for drug and nutrient safety and efficacy testing.
|Voeding en serumcholesterol.
Beynen, A.C. - \ 1989
In: Cholesterol... te beheersen of niet? / Masereeuw, R., - p. 28 - 30.