A glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier

• Published in: Nature communications 2019-08, Vol.10 (1), p.3656-17, Article 3656
• Main Authors: Petrosyan, Astgik, Cravedi, Paolo, Villani, Valentina, Angeletti, Andrea, Manrique, Joaquin, Renieri, Alessandra, De Filippo, Roger E., Perin, Laura, Da Sacco, Stefano
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/106; 13/31; 13/51; 13/62; 14/19; 14/28; 14/34; 14/63; 147/135; 631/1647/277; 631/443/272/1684/1587; 82/16; 96/106; 96/63; Albumins - metabolism; Albuminuria - drug therapy; Albuminuria - metabolism; Amniotic fluid; Autoantibodies; Cells, Immobilized - chemistry; Cells, Immobilized - metabolism; Chemical compounds; Chips; Collagen; Cytology; Diaphragm; Endothelial cells; Endothelial Cells - chemistry; Endothelial Cells - metabolism; Endothelium; Filtration; Glomerulus; Heparan sulfate; High-throughput screening; Humanities and Social Sciences; Humans; Kidney diseases; Kidney Glomerulus - chemistry; Kidney Glomerulus - drug effects; Kidney Glomerulus - metabolism; Lab-On-A-Chip Devices; Laboratories; Male; Microfluidics; Morphology; multidisciplinary; Nephritis, Hereditary - drug therapy; Nephritis, Hereditary - metabolism; Nephrology; Pharmacology; Podocytes - chemistry; Podocytes - metabolism; Proteins; Proteinuria; Science; Science (multidisciplinary); Target recognition; Therapeutic applications; Urology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11577-z

In this work we model the glomerular filtration barrier, the structure responsible for filtering the blood and preventing the loss of proteins, using human podocytes and glomerular endothelial cells seeded into microfluidic chips. In long-term cultures, cells maintain their morphology, form capillary-like structures and express slit diaphragm proteins. This system recapitulates functions and structure of the glomerulus, including permselectivity. When exposed to sera from patients with anti-podocyte autoantibodies, the chips show albuminuria proportional to patients’ proteinuria, phenomenon not observed with sera from healthy controls or individuals with primary podocyte defects. We also show its applicability for renal disease modeling and drug testing. A total of 2000 independent chips were analyzed, supporting high reproducibility and validation of the system for high-throughput screening of therapeutic compounds. The study of the patho-physiology of the glomerulus and identification of therapeutic targets are also feasible using this chip. The glomerular filtration barrier is a complex structure in charge of renal ultrafiltration. Here the authors present a glomerulus-on-a-chip for disease modelling and high-throughput drug screening where human podocytes and human glomerular endothelial cells are separated by an extracellular matrix resembling the in vivo basement membrane.