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March 05, 2020

A new chemical expands kidney cells differentiated from stem cells

The Kenji Osafune laboratory discovers that the chemical compound TCS21311 can replace a key growth factor in the expansion of kidney cells differentiated from human iPS cells.

Cell therapies offer a substitute for kidney transplants, which are the most effective treatment for kidney failure, but according to the National Kidney Foundation in the U.S., serve approximately only 10% of patients due to donor shortages. In efforts to advance cell therapies for the kidney, Professor Kenji Osafune and his team of researchers report that replacing a key growth factor with a chemical compound called TCS21311 could simplify the expansion of nephron progenitor cells differentiated from iPS cells by modulating JAK3-STAT3 signaling.

In kidney cell therapies, the creation of nephron progenitor cells is key. These cells form many components of the nephron, which marks the minimal functional unit of the kidney. One challenge for kidney cell therapies has been to produce a sufficient number of nephron progenitor cells. Researchers have had success expanding nephron progenitor cells differentiated from stem cells with a cocktail of factors. Notably, all these cocktails include bone morphogenetic protein (BMP)7. As its name suggests, BMP7 is critical for bone formation, but it also is recognized as a key determinant of the kidney.

In the expansion of human iPS cell-derived nephron progenitor cells, researchers have explored the key signaling pathways regulated by BMP7 by substituting this factor with small chemical compounds.

"The role of BMP7 in nephron progenitor cell development is not well understood. BMP7 interacts with several essential signaling molecules like Smads and MAPK. Using small molecules, we also found it regulates JAK3-STAT3 signaling," says Osafune.

JAK3-STAT3 signaling is important for gene activations and is associated with fundamental cell behavior like division and growth.

The discovery of JAK3-STAT3 signaling in nephron progenitor cell expansion was made by finding that the replacement of BMP7 with TCS21311, a JAK3 inhibitor, in expansion cultures still led to an efficient production of nephron progenitor cells. Further study revealed that the effect possibly depended on inhibiting Smad7 molecules.

"The discovery of TCS21311 and JAK3-STAT3 signaling will reduce the workload in preparing nephron progenitor cells from iPS cells for regenerative therapies," says Osafune.

Paper Details
  • Journal: Biochemical and Biophysical Research Communications
  • Title: Small molecule TCS21311 can replace BMP7 and facilitate cell proliferation in in vitro expansion culture of nephron progenitor cells
  • Authors: Hiraku Tsujimoto, Toshikazu Araoka, Yohei Nishi, Akira Ohta, Tatsutoshi Nakahata
    and Kenji Osafune
  • Author Affiliations: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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