Mini kidneys grown from stem cells

Monday, 02 September, 2019

Mini kidneys grown from stem cells

An international team of researchers led by Nanyang Technological University, Singapore has grown ‘miniature kidneys’ (known as kidney organoids) in the laboratory that could be used to better understand how kidney diseases develop in individual patients. The research was described in the journal Cell Stem Cell.

Seeking to study the effects of genetic polycystic kidney disease — one of the most common inherited causes of kidney failure in adults — Assistant Professor Xia Yun and her team took regular adult cells from an adult patient with the disease and genetically reprogrammed them into stem cells, as the adult human body does not have any kidney stem cells. Two essential chemicals were then added to direct these induced pluripotent stem cells to grow into kidney organoids.

Four to five weeks later, these organoids developed fluid-filled cysts that are characteristic of the disease. This signalled that they were ready to be used to test the efficacy of two drug molecules with potential for treating genetic polycystic kidney disease.

Existing approaches to testing potential treatments through such ‘drug screening’ do not take account of the fact that the genetic errors that cause kidney diseases vary from patient to patient. By generating induced pluripotent stem cells from an adult patient with a genetic kidney disease, and then growing kidney organoids from them, the research team has thus paved the way for tailoring treatment plans specific to each patient.

“A patient’s genetic make-up is closely intertwined with how their kidney disease will develop, as the type of mutation within the disease-causing gene can differ from patient to patient,” said Asst Prof Xia, from the NTU Lee Kong Chian School of Medicine (LKCMedicine).

“Our kidney organoids, grown from the cells of a patient with inherited polycystic kidney disease, have allowed us to find out which drugs will be most effective for this specific patient. We believe that this approach can be extended to study many other types of kidney disease, such as diabetic nephropathy.”

Insights into human kidney development

The same approach can be employed to generate kidney organoids from stem cells derived from healthy individuals. When these kidney organoids were implanted into mice, the blood vessel network of these mini kidneys successfully connected with the host mice circulation system and developed a more mature architecture capable of preliminary filtration and reabsorption.

The team’s kidney organoids may thus offer new insights into human kidney development, which currently cannot be studied in depth due to concerns surrounding human stem cell research. While the origin of kidney blood vessel networks is not fully known, it is widely accepted that a type of stem cell known as ‘vascular progenitors’ is involved in their formation by developing into blood vessel cells.

By examining the genetic information within single cells of the organoid, the NTU-led team also discovered a new source of stem cells that contribute to making these blood vessel networks: nephron progenitor cells. Prior to this discovery, these cells were known only as precursors to nephrons, the kidney’s filtering units.

“We observed very robust and consistent development of blood vessel networks within our kidney organoids, which opens new doors to investigate the developmental origin of renal blood vessel networks, which is still not fully understood,” said NTU LKCMedicine Assistant Professor Foo Jia Nee. “Using this novel organoid platform, we unexpectedly discovered a new source of renal blood vessels that may improve our understanding of kidney development.”

The mini kidneys may also be used to better understand the development of nephrons in the kidney. The number of nephrons at birth is inversely correlated with incidence of hypertension and kidney failure later in life. Being born with a high nephron number appears to provide some degree of protection against these conditions.

“A thorough understanding of human embryonic kidney development, especially how environmental factors influence the process, may help us develop ways to promote a high birth nephron number for foetuses as they develop during pregnancy,” Asst Prof Xia said.

Also serving on the study was world-renowned stem cell scientist Professor Juan Carlos Izpisua Belmonte, from the Salk Institute for Biological Studies in California. He added, “Although we are still quite far away from using these kidney organoids for replacement therapy, this study has made a small step closer to this ultimate goal.”

Image caption: An image of a kidney organoid at Day 24 under confocal microscopy, which shows the preliminary development of structures in a kidney.

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