Researchers at the Ecole Polytechnique Fédérale de Lausanne in Switzerland developed two complementary benchtop bladder models that could help in understanding the mechanisms behind recurring urinary tract infections (UTIs). The first involves bladder organoids, which allow the researchers to study bacterial-bladder cell interactions under realistic conditions, which include the 3D multi-layered architecture of the bladder wall. The second is a bladder-on-a-chip, which includes additional features that mimic the bladder environment, including the mechanical effects of bladder filling and voiding and bladder vasculature.
UTIs are a common infection, which can frequently reoccur, even after treatment using antibiotics. The infections are typically caused by a type of E. coli bacteria. With drug-resistant bacteria on the rise, understanding how and why UTIs reoccur is important. To date, researchers have been aware that persistent microbial communities can reside in the bladder, and when they begin to proliferate they can invade and kill so-called umbrella cells that line the bladder. The bacteria can then penetrate deeper into the bladder wall, helping them to hide from antibiotics and cause recurrent UTIs.
Studying these processes in detail is difficult in experimental animals or using standard tissue culture techniques. “Infection dynamics are difficult to capture from static imaging of tissue explants at serial time points,” said Kunal Sharma, a researcher involved in the project, in a press release. “Thus far, in vitro models have not recapitulated bladder architecture with sufficient fidelity to study the time course of these events.”
These new complementary bladder models are intended to assist researchers in gaining new insights into infection dynamics in the bladder. The first model includes bladder organoids that mimic the epithelial architecture of the bladder.
“By generating organoids from a mouse with a fluorescent label incorporated within cell membranes, we could use live-cell confocal imaging at EPFL’s BioImaging & Optics Core Facility to identify specific bacterial niches within the organoid with a high spatial resolution,” said Sharma. “By imaging multiple organoids, we managed to identify heterogeneity and diverse outcomes of host-pathogen interactions. This proof-of-concept system has shown promising potential for follow up studies on bacterial persistence to antibiotics and the dynamics of immune cell responses to infection.”
The second model is a bladder-on-a-chip that includes endothelial cells and umbrella cells that grow together under conditions that closely mimic the bladder, including a simulated urine flow and mechanical forces to simulate the expansion and contraction the bladder experiences as it fills and empties of urine.
“Microphysiological models bridge the gap between simple cell culture systems and animal models,” said Vivek Thacker, another researcher involved in the study. “The two models complement each other well and are tailored to study specific aspects of the disease. We hope they will serve as a resource for the wider microbiology community and advance the synergies between the tissue engineering and infectious diseases communities.”
Study in journal eLife: Dynamic persistence of UPEC intracellular bacterial communities in a human bladder-chip model of urinary tract infection