3D rendering of multiple Induced Pluripotent Stem Cells - iPSCs
Credit: Marcin Klapczynski / iStock

Pluripotent stem cell (PSC) therapies have shown great promise across a number of diseases, including heart disease, diabetes, and cystic fibrosis, but have been plagued by them often leading to cancer after transplantation. Now, a team of researchers from the Nara Institute of Science and Technology in Japan have identified a protein called EPHA2 that may be a key in preventing tumorigenesis of PSCs after transplantation.

“Our findings present advancements that could bridge the gap between stem cell research and clinical application,” said Atsushi Intoh, PhD, an assistant professor of stem cell technology at the Nara Institute and lead author of the research published in Stem Cells Translational Medicine.

Prior to this study, the Nara Institute team had found that EPHA2 is elevated in PSCs prior to differentiation. Conducting further studies using both mouse and human stem cell cultures, the investigators discovered that EPHA2 in stems cells is co-expressed with OCT4, a transcription factor protein that controls the expression of gene involved in the differentiation of stems. In an eye-opening discovery, the team found that when they knocked down the EPHA2 gene from the cells, cultured stem cells spontaneously differentiated, suggesting that EPHA2 plays a key role in preserving stem cells in an undifferentiated state.

The researchers hypothesized that EPHA2-expressing stem cells that would fail to differentiate, could be responsible for the tumorigenesis often observed when PSCs are transplanted into the target organ. To test this, PSC cultures were prepared and then artificially induced to differentiate into liver cells. The team used a magnetic antibody that targets EPHA2 to extract EPHA2-positive cells form a group of cultures prior to transplanting them into mouse models. This resulted into vastly suppressed tumor formation in the mice receiving transplants form the cultures where EPHA2 had been removed.

“EPHA2 conclusively emerges as a potential marker for selecting undifferentiated stem cells, providing a valuable method to decrease tumorigenesis risks after stem cell transplantation in regenerative treatments,” said corresponding author Akira Kurisaki, PhD, professor of stem cell technology at the Nara Institute.

Using this new finding the researchers believe additional in-depth studies of EPHA2 could lead to protocols to control the activity of the protein to ultimately make the use of PSCs safer for therapies to repair damaged organs and potentially treat degenerative diseases.

“This research positions EPHA2 as a promising cell surface marker for undifferentiated and tumorigenic stem cells in both mouse and human,” the researchers concluded. “The potential of EPHA2 to mitigate the risk of tumorigenesis highlights the significance in advancing the safety of stem cell transplantation for regenerative medicine applications.”

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