Kidney Organoids Created with Working Blood Vessels

Capillary, in red, developing in a glomerulus in a kidney organoid. (Wyss Institute, Harvard University)

11 Feb. 2019. Bioengineering labs at Harvard University and affiliated hospitals used stem cells and three-dimensional printing to create kidney tissue chips with blood vessel networks. A team from Harvard’s engineering school, Wyss Institute for Biologically Inspired Engineering, and Brigham and Women’s Hospital in Boston, affiliated with Harvard Medical School, describes the process in today’s issue of the journal Nature Methods (paid subscription required).

Researchers led by bioengineer Jennifer Lewis at the Wyss Institute and stem cell biologist Ryuji Morizane at Brigham and Women’s are seeking to advance lab-produced kidney tissue to make it a better tool for drug testing, developing models for kidney disease or injury, and eventually for regeneration. Morizone with co-author Joseph Bonventre who studies kidney regeneration at Brigham and Women’s, created in 2015 pieces of 3-D kidney tissue called organoids from induced pluripotent, or adult, stem cells on a microfluidic or lab-on-a-chip device.

While considered a key advance in kidney regeneration, these early organoids had only rudimentary blood vessel development, which make the devices less useful tools for drug testing or disease modeling. Since their initial organoid chip, other researchers found implanting these pieces of kidney in animals helped mature the tissue, including blood vessels. The team hypothesized that mechanical forces in mammals’ bodies helped the kidney tissue develop, and the researchers devised a process for emulating that environment in the lab.

That process adapted techniques for 3-D bioprinting developed by Lewis and Wyss Institute colleagues. As reported by Science & Enterprise in October 2016, Wyss Institute researchers led by Lewis devised a 3-D printing technique to produce organ tissue chips with built-in sensors, starting with heart tissue. In the new project, the researchers used 3-D bioprinting to create kidney organoids in a liquid-flow environment simulating the mechanical forces in a mammalian body. The results show the beginning of blood vessels forming, including tiny capillaries, in kidney organoids.

As the kidney organoid chips made in the dynamic fluid environment matured, the researchers found blood vessels develop in glomeruli, tiny components in kidney cells that filter blood. In addition, tubules that connect to glomeruli and flow the filtered waste into urine, and cells that prevent plasma proteins from entering the urine called podocytes matured more than comparison static-environment organoids. Moreover, kidney tissue cells in the 3-D printed organoids had more mature gene expression than static-environment organoids.

“This important advance opens up new avenues for accurately testing drug toxicity in vitro in differentiated nephron compartments and modeling kidney diseases, like polycystic kidney disease, that affect specific structures and cell types using patient-derived stem cells as the starting point,” says Lewis in a Wyss Institute and university statement. “Our method may pave the way to also vascularize other types of organoids, such as the liver organoids.”

Morizane and Bonventre applied for a patent for creating human kidney tissue from stem cells. Bonventre is also a co-founder of the biotechnology company Goldfinch Bio in Cambridge, Massachusetts developing precision therapies for chronic kidney disease. Lewis is co-founder of the company Voxel8 Inc. in Somerville, Massachusetts, an additive manufacturer — the industrial form of 3-D printing — of customized athletic footwear and apparel.

The following video tells more about blood vessel development in kidney organoids.

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