TY - JOUR
T1 - Development and validation of bioengineered intestinal tubules for translational research aimed at safety and efficacy testing of drugs and nutrients
AU - Jochems, Paulus G M
AU - van Bergenhenegouwen, Jeroen
AU - van Genderen, Anne Metje
AU - Eis, Sophie T
AU - Wilod Versprille, Livia J F
AU - Wichers, Harry J
AU - Jeurink, Prescilla V
AU - Garssen, Johan
AU - Masereeuw, Rosalinde
N1 - Copyright © 2019. Published by Elsevier Ltd.
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
KW - Caco-2
KW - Small intestine
KW - In vitro
KW - Microfluidic and screening
U2 - 10.1016/j.tiv.2019.04.019
DO - 10.1016/j.tiv.2019.04.019
M3 - Article
C2 - 31071426
SN - 0887-2333
VL - 60
SP - 1
EP - 11
JO - Toxicology in Vitro
JF - Toxicology in Vitro
ER -