We unveiled the role of a previously unrecognized pathway that is important for maintaining the stem cell state,” says Carla M. Koehler, Ph.D., professor of chemistry and biochemistry at the University of California, Los Angeles. In a chemical screen that proposed to identify inhibitors of the mitochondrial FAD-linked sulfhydryl oxidase Erv1, essential for mitochondrial biogenesis and cell survival, Dr. Koehler and her colleagues identified MitoBloCK-6, a small molecule that selectively inhibits the mitochondrial redox-mediated import of Erv1 substrates.
Despite its ability to inhibit Erv1 and its human homolog ALR in vitro, MitoBloCK-6 did not affect the in vivo growth and function of differentiated cells but, surprisingly, caused apoptosis in pluripotent human embryonic stem cells.
“When we differentiated stem cells they were no longer susceptible, and when we reprogrammed them to the pluripotent state, they again became susceptible to this compound,” she says.
MitoBloCK-6 is an attractive option to remove undifferentiated stem cells from differentiated cell populations, and presents multiple advantages over existing protocols. “We are further exploring this compound, and hope that it can be used at a certain time during the differentiation protocol to allow the removal of cells that failed to differentiate, without affecting the ones that became committed to become specific cell types,” Dr. Koehler adds.
This finding has an additional, more profound significance that extends beyond the field of stem cell biology, as it underscores the cardinal position that basic research plays in advancing translational research.
“There are so many aspects that we do not understand about the function of many cellular pathways at the basic level, and it is difficult to explore the endpoint without performing and trying to understand the basic research. In this case, we are still trying to understand why mitochondria are important for stem cell survival,” Dr. Koehler says.
Basic and translational research in stem cell biology and regenerative medicine are witnessing an exciting time. More than 5,000 clinical trials on stem cell therapies are currently under way globally, promising to revolutionize therapeutic prospects. As our knowledge about differentiation and regeneration is advancing, it is essential to appreciate and capitalize on the interdiscliplinary spirit that has become a defining feature of this vibrant and fascinating field.