A glomerulus–on–a–chip lined by human stem cell–derived kidney cells could help model patient–specific kidney diseases and guide therapeutic discovery.
Podocytes are the target of many congenital or acquired kidney diseases, and they are often harmed by drugs.

To build an in vitro model of the human glomerulus that could allow probing deeper into its function, as well as its vulnerabilities to disease and drug toxicities, researchers have been attempting to engineer human stem cells – that in theory can give rise to any mature cell type – so that they form into functional podocytes. These cell culture efforts, however, so far have failed to produce populations of mature podocytes pure enough as to be useful for modeling glomerular filtration.

A team led by Donald Ingber, MD, PhD, at Harvard’s Wyss Institute for Biologically Inspired Engineering now reports a solution to this challenge in Nature Biomedical Engineering, which enables the differentiation of human induced pluripotent stem (iPS) cells into mature podocytes with more than 90% efficiency. Linking the differentiation process with organ–on–a–chip technology pioneered by his team, the researchers went on to engineer the first in vitro model of the human glomerulus, demonstrating effective and selective filtration of blood proteins and podocyte toxicity induced by a chemotherapy drug in vitro. Ingber is the Wyss Institute’s Founding Director, the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).

Ingber’s team has engineered multiple organs–on–chips that accurately mimic human tissue and organ–level physiology and that are currently being evaluated by the Food and Drug Administration (FDA) as a tool to more effectively study the effects of potential chemical and biological hazards found in foods, cosmetics or dietary supplements than existing culture systems or animal models. In 2013, his team developed an organ–on–a–chip microfluidic culture device that modeled the human kidney’s proximal tubule, which is anatomically connected to the glomerulus and salvages ions from urinary fluid. Now, with the team’s newly engineered human kidney glomerulus–on–a–chip, researchers also can get in vitro access to the kidney’s core filtration mechanisms that are critical for drug clearance and pharmacokinetics, in addition to studying human podocytes at work.

To generate almost pure populations of human podocytes in cell culture, Samira Musah, PhD, the study’s first author and HMS Dean’s Postdoctoral Fellow who is working with Ingber at the Wyss Institute, leveraged pieces of the stem cell biologists’ arsenal, and merged them with snippets taken from Ingber’s past research on how cells in the body respond to adhesive factors and physical forces in their tissue environments.

“Our method not only uses soluble factors that guide kidney development in the embryo, but, by growing and differentiating stem cells on extracellular matrix components that are also contained in the membrane separating the glomerular blood and urinary systems, we more closely mimic the natural environment in which podocytes are induced and mature,” said Musah. “We even succeeded in inducing much of this differentiation process within a channel of the microfluidic chip, where by applying cyclical motions that mimic the rhythmic deformations living glomeruli experience due to pressure pulses generated by each heartbeat, we achieve even greater maturation efficiencies.”