A research team at Sanford Burnham Prebys demonstrated that the transcription factor OCT4 can induce stem cells to specialize via signal-induced differentiation.
In a new study, scientists at Sanford Burnham Prebys Medical Discovery Institute (CA, USA) demonstrated that the protein OCT4 narrows down the range of cell types that stem cells can differentiate into. The findings could impact efforts to produce specific types of cells for future therapies to treat a broad range of diseases, as well as aid the understanding of which cells are affected by drugs that influence cell specialization. The study was recently published in Molecular Cell.
As an organism develops from its earliest form into maturity, its cells transition from being unspecialized stem cells to differentiated cells that make up its tissues. Numerous labs are currently attempting to mimic this process to generate specific types of cells that could be transplanted into patients to treat various diseases.
OCT4 is a transcription factor that maintains stem cells’ ability to give rise to any tissue in the body. OCT4 works by sitting on DNA and recruiting factors that either help initiate or repress the transcription of specific genes.
“We found that the stem cell-specific protein OCT4 primes certain genes that, when activated, cause the cell to differentiate, or become more specialized,” explained Laszlo Nagy, professor and director of the Genomic Control of Metabolism Program and senior author of the study. “This priming customizes stem cells’ responses to signals that induce differentiation and makes the underlying genetic process more efficient.”
The new study demonstrates that OCT4 also collaborates with transcription factors that are activated by external signals, such as the retinoic acid (vitamin A) receptor (RAR) and beta-catenin, to activate their respective genes. Retinoic acid induces the differentiation of stem cells into neuronal precursors, and activation of beta-catenin by Wnt can either support pluripotency or promote non-neural differentiation, depending on which other signals are present. Recruitment of these factors ‘primes’ a subset of the genes that the signal-responsive factors can activate.
“Our findings suggest a general principle for how the same differentiation signal induces distinct transitions in various types of cells,” added Nagy. “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,” commented Nagy. “Now we plan to explore whether other transcription factors behave similarly to OCT4–that is, to find the code in more mature cell types.”
http://beaker.sbpdiscovery.org/2016/08/breakthrough-in-understanding-how-stem-cells-become-specialized/; Zoltan Simandi, Attila Horvath, Lyndsey C. Wright et al. OCT4 Acts as an Integrator of Pluripotency and Signal-Induced Differentiation. Molecular Cell doi: http://dx.doi.org/10.1016/j.molcel.2016.06.039 (2016) (Online before print)