Stem cells can customize their responses to external cues, effectively priming themselves to differentiate toward one cell fate or another. Curiously, the same cues can have different effects on different stem cells, rather like the same speed-dial buttons can instigate calls to different numbers, depending on how the phone has been programmed.
Stem cells don’t come with a speed-dial instruction manual, so scientists based at Stanford Burnham Prebys Medical Discovery Institute (SPB) have been working to hack the code. In fact, these scientists have already discovered that OCT4, a stem cell-specific transcription factor, can narrow the range of cell types that stem cells can become.
This finding appeared August 4 in the journal Molecular Cell, in an article entitled, “OCT4 Acts as an Integrator of Pluripotency and Signal-Induced Differentiation.” The article described how the SPB team used genomic approaches along with loss- and gain-of-function genetic models to “uncover OCT4 as an integral and necessary component of signal-regulated transcriptional processes required for tissue-specific responses.”
“OCT4 binds a large set of low-accessible genomic regions,” wrote the article’s authors. “At these sites, OCT4 is required for proper enhancer and gene activation by recruiting co-regulators and RAR:RXR [retinoic acid receptor:retinoid X receptor heterodimer] or β-catenin, suggesting an unexpected collaboration between the lineage-determining transcription factor and these differentiation-initiating, signal-dependent transcription factors.”
The SPB scientists also tested the idea that OCT4 can reprogram a cell-type-specific signal response. They demonstrated that overexpression of OCT4 in a kidney cell line is sufficient for signal-dependent activation of otherwise unresponsive genes in these cells.
“We found that the stem-cell-specific protein OCT4 primes certain genes that, when activated, cause the cell to differentiate, or become more specialized,” said Laszlo Nagy, M.D., Ph.D., a professor at SPB and the senior author of the current study. “This priming customizes stem cells' responses to signals that induce differentiation and makes the underlying genetic process more efficient.”
Essentially, the new study shows that, at certain genes, OCT4 can collaborate with transcription factors that are activated by external signals, such as the retinoic acid (vitamin A) receptor and β-catenin, to turn on their respective genes. Vitamin A converts stem cells to neuronal precursors, and activation of β-catenin by Wnt can either support pluripotency or promote nonneural differentiation, depending on what 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,” explained Dr. 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—remain 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,” continued Dr. 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.
“If other factors also have this dual function—both maintaining the current state and 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.”