Sanford Burnham Prebys Medical Discovery Institute scientists have made an impressive advance in helping us to better understand how the cells of an organism, which are made up of the same genetic information, can come to be so diverse. A study was published in Molecular Cell Journal showing that a protein named OCT4 completely narrows down the range of cell types that stem cells are able to turn into. This discovery could impact efforts working hard to produce specific types of cells for the treatment of a broad range of disease and may also be able to help in the understanding of which cells are affected by drugs that directly influence cell specialization.

Laszlo Nagy, professor and director of the Genomic Control of Metabolism Program and senior author of the study says we have found that the stem cell specific protein OCT4 primes certain genes that, when activated, cause the cell to differentiate, or become more specialized. This priming customizes stem cells’ responses to signals that induce differentiation and makes the underlying genetic process more efficient.

As an organism starts to develop from its simplest and most earliest form of maturity, its cells transition from a state of high flexibility (stem cells) to more specialized types that make up its tissues. Many labs are constantly working hard to be able to replicate this process to generate specific types of cells that could be directly implanted into patients in order to treat a wide range of diseases. Pancreatic beta cells, for example, hold the potential to be able to treat diabetes and neurons that produce dopamine could treat Parkinson’s.

OCT4 is what is known as a transcription factor (a protein that regulates the activity of surrounding genes) which maintains the ability of stem cells to give rise to any tissue throughout the entire body. OCT4 works by attaching to DNA and recruiting factors that will either help to initiate or repress the reading of certain genes.

The new study has uncovered that at certain genes, OCT4 also works in collaboration with transcription factors that are activated by signals externally in order to turn on their respective genes. Vitamin A converts stem cells to neuronal precursors and when beta-catenin by Wnt is activated it can either support pluripotency or non-neural differentiation. This depends directly upon what other signals are present at the time. Recruitment of these factors prepares a subset of the genes that the signal responsive factors are then able to activate.

Nagy says our findings suggest a general principle for how the same differentiation signal induces distinct transitions in various types of cells. Whereas in stem cells, OCT4 recruits the RAR to neuronal genes, in bone marrow cells, another transcription factor would recruit RAR to genes for the granulocyte program. Which factors determine the effects of differentiation signals in bone marrow cells and other cell types remains to be determined. In a sense we’ve found the code for stem cells that links the input, signals like Vitamin A and Wnt, to the output cell type. Now we plan to explore whether other transcription factors behave similarly to OCT4. That is, to find the code in more mature cell types. If other factors also have this dual function, both maintaining the current state of priming certain genes to respond to external signals, that would answer a key question in developmental biology and advance the field of stem cell research.