To be or not to be a stem cell: Sanford-Burnham lab finds new mechanism

Chemical modification of genetic material (RNA, shown here) helps keep stem cells in their “ground state”, study finds

The year is a mere 14 days old and yet my colleagues have already blogged here about very positive news regarding CIRM-funded stem cell-based clinical trial projects for treating heart disease and sickle cell anemia. At times like these, it’s good to take a step back and keep in mind that these projects didn’t materialize overnight. Instead, they began with basic research that helped pave the road to the clinic.

And the steady drum of basic stem cell research keeps beating in 2014. Just last week Dr. Crystal Zhao’s lab at the Sanford-Burnham Medical Research Institute reported in Nature Cell Biology that they’ve identified a new molecular mechanism that helps keep embryonic stem cells in their stem cell state rather than maturing into specialized cell types. The lead author, Dr. Yang Wang, is a CIRM Research Training scholar.

Now don’t let the word “basic” in basic research fool you. This laboratory work is incredibly intricate requiring deep understanding, insightful thinking, and years of plugging away at fundamental questions of the inner workings of cells. The Sanford-Burnham team focused on the unique fork-in-the-road decision that each embryonic stem cell can make based on cues from its environment: (1) do I make copies of myself and maintain the ability to become any cell type (scientists call this pluripotency: pluri = many; potent = powerful)? or (2) do I mature into a specialized cell type like a heart muscle or liver cell?

Zhao’s lab zeroed in on two specific enzymes within the cell, called methylases, which decorate the cells’ genetic material with chemical tags. The team showed that these methylases could tag the genetic code that’s responsible for maturing a stem cell into a specialized cell type. It turns out that when this chemical tagging occurs the genetic material becomes unstable and degrades and so the stem cell maintains its “ground state” and doesn’t mature. The team demonstrated this property using some genetic engineering tactics: the team depleted the two methylases from the cell. Now, with no chemical tagging, the genetic material remained stable and was able to drive the cells towards a mature cell type.

Like a lot of basic research, the application of this discovery to a stem cell therapy may not jump out at you. Still, by clearly understanding the molecular basis for what makes a stem cell maintain its “stemness”, scientists can develop more consistent batches of stem cells that could be used for manufacturing stem cell-based therapies for a wider and wider patient population. As Dr. Wang points out:

Embryonic stem cells … have great potential in therapeutic application but how stem cells maintain pluripotency is still largely unknown. To understand the mechanisms for keeping stem cells in a ground state is important for establishing systematical standards of stem cells, leading to advanced methods for expanding stem cells and generating new protocols to [mature] stem cells.

So while we celebrate the recent clinical trial updates here in 2014, the basic research also being done today may help keep the stem cell party thriving in 2024 and beyond.

CIRM Funding: Research Training II (TG2-01162) 

Todd Dubnicoff

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