A Korean research team has, for the first time, uncovered the regulatory mechanism of a key protein that determines stem cell quality.
The findings provide new clues for overcoming quality deterioration during large-scale cell culture, raising expectations for the development of higher-quality cell therapies.
Asan Medical Center (AMC) said Wednesday that a joint research team from the hospital and the University of Ulsan College of Medicine identified the molecular mechanism that stabilizes Dnmt3L, a critical protein responsible for maintaining stem cell identity and differentiation capacity.
From left, Professor Shin Dong-myung, Dr. Lee Seung-un and Professor Kim Kyung-gon. (Courtesy of AMC)
The study was conducted by Professor Shin Dong-myung and Dr. Lee Seung-un of the Department of Cellular and Genetic Engineering at AMC, along with Professor Kim Kyung-gon from the Department of Biomedical Informatics.
Dnmt3L plays a crucial role in determining stem cell quality and differentiation potential, but it is highly susceptible to degradation under different culture conditions. To investigate this, the researchers analyzed gene expression patterns across various culture environments and tracked molecular-level changes using mass spectrometry-based protein analysis.
The team found that acetylation at specific amino acid residues -- K238 and K412 -- within Dnmt3L inhibits protein degradation, leading to excessive accumulation of the protein in cells.
In addition, co-immunoprecipitation (Co-IP) experiments revealed that Prdm14 and G9a -- proteins involved in maintaining stem cell properties -- directly bind to Dnmt3L, suppress its acetylation and promote its degradation. The findings demonstrate that a specific protein complex functions as a regulator of genetic stability in stem cells.
Further functional validation showed that stem cells with increased acetylation gradually developed disrupted DNA methylation patterns over time and exhibited significantly reduced efficiency in differentiating into neural or cardiac cells compared with normal stem cells. The results suggest that the acetylation status of Dnmt3L could serve as a key indicator of stem cell quality.
Professor Shin said, “This study is significant because it identifies, at the molecular level, the causes of epigenetic instability and quality deterioration -- long-standing challenges in stem cell culture. Based on these findings, we expect to improve differentiation efficiency into specific cell types and contribute to the large-scale production of high-quality, patient-specific cell therapies, ultimately enhancing the safety of regenerative medicine.”
The study was supported by government funding, including the pan-ministerial regenerative medicine R&D program, and was
published
in the latest issue of Experimental & Molecular Medicine.
Kim Ji-hye
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