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User-friendly microfluidic system reveals native-like morphological and transcriptomic phenotypes induced by shear stress in proximal tubule epithelium

Authors :
Natalie N. Khalil
Andrew P. Petersen
Cheng J. Song
Yibu Chen
Kaelyn Takamoto
Austin C. Kellogg
Elaine Zhelan Chen
Andrew P. McMahon
Megan L. McCain
Source :
APL Bioengineering, Vol 7, Iss 3, Pp 036106-036106-10 (2023)
Publication Year :
2023
Publisher :
AIP Publishing LLC, 2023.

Abstract

Drug-induced nephrotoxicity is a leading cause of drug attrition, partly due to the limited relevance of pre-clinical models of the proximal tubule. Culturing proximal tubule epithelial cells (PTECs) under fluid flow to mimic physiological shear stress has been shown to improve select phenotypes, but existing flow systems are expensive and difficult to implement by non-experts in microfluidics. Here, we designed and fabricated an accessible and modular flow system for culturing PTECs under physiological shear stress, which induced native-like cuboidal morphology, downregulated pathways associated with hypoxia, stress, and injury, and upregulated xenobiotic metabolism pathways. We also compared the expression profiles of shear-dependent genes in our in vitro PTEC tissues to that of ex vivo proximal tubules and observed stronger clustering between ex vivo proximal tubules and PTECs under physiological shear stress relative to PTECs under negligible shear stress. Together, these data illustrate the utility of our user-friendly flow system and highlight the role of shear stress in promoting native-like morphological and transcriptomic phenotypes in PTECs in vitro, which is critical for developing more relevant pre-clinical models of the proximal tubule for drug screening or disease modeling.

Details

Language :
English
ISSN :
24732877
Volume :
7
Issue :
3
Database :
Directory of Open Access Journals
Journal :
APL Bioengineering
Publication Type :
Academic Journal
Accession number :
edsdoj.2102ffe3666e4b4db2feed8152640442
Document Type :
article
Full Text :
https://doi.org/10.1063/5.0143614