A new way to wind the development clock of cardiac muscle cells

These days, scientists can collect a few skin or blood cells, wipe out their identities, and reprogram them to become virtually any other kind of cell in the human body, from neurons to heart cells.   

The journey from skin cell to  another type of  functional cell involves converting them into induced pluripotent stem cells (iPSCs), which  are  similar to the developmentally immature  stem  cells found in embryos, and then coaxing them to mature into  something different.  

But the process  runs on an invisible clock, one in which scientists are interested in speeding up  so adult-like cells are available when needed, whether for testing drugs for precision medicine, transplanting to repair injury or defect, or better understanding basic biology.  It involves an FDA-approved compound called polyinosine- polycytidylic  acid, or  pIC , a double-stranded RNA molecule that activates a cell’s innate defense system. The compound is commonly used to boost vaccines and chemotherapy. The researchers found that when added to induced pluripotent stem cells undergoing the process of transitioning into cardiac muscle cells,  pIC  accelerated cellular maturation.  

"We make beating heart muscle cells out of human  iPSCs  because we are interested in  understanding and treating  cardiac diseases," says lead author and  University of Wisconsin-Madison  MD-PhD  student, Mitch Biermann. "It’s important that the cells  we make in a dish are as  close to adult heart muscle function as we can make them. "  

This is because, study leader Tim Kamp says, immature cardiac cells don’t contract as strongly as adult cardiac cells, and the electrical  properties  that sets their beat is different.  Their metabolic characteristics are a bit different, too.  

"If you want  to know how  drugs, such as  beta blockers ,  work in the adult heart, it’s better to test those in more mature ,  human iPSC-derived cardiomyocytes (cardiac muscle cells)," says Kamp, director of the University of Wisconsin-Madison Stem Cell and Regenerative Medicine and a professor of medicine in the School of Medicine and Public Health.  

Other researchers have made progress utilizing a variety of ways to speed up the process, including electrical stimulation, changes to the metabolic environment of the cells, and even forcing the cells into the rod-like shapes more characteristic of adult cells, but each method seems to fall a bit short.  

Biermann  chose  a different  tack. He noticed that cardiac cells derived from i PSCs  mature at different rates  in a dish.  O ther researchers found that cardiomyocytes  in  the heart and in blood vessels  of rats  matured  according to the same clock , despite  being  distan t   from each other in the body.  

" Maturation isn’t only controlled by what’s going  on in the  environment of the  heart," Biermann says. "Because of that and because maturation in a dish seems random, we  started thinking about  epigenetics."   

In other words, Biermann thought maturation rates might have to do with the way timing of cellular  maturation  events was coordina ted. He w ondered  whether he could essentially prime the cells  at just the right time  to  accelerate  maturation  --  to  wind up the clock  --  and began looking for compounds that did  so  without also killing  them.  

That’s how he found  pIC. When he added it to early cardiac  precursor  cells in the lab, they  formed  beating  heart cells  two days sooner than cells without  pIC. After 48 hours, the c ells were removed from the compound  but its effects continued to linger, leading to cells that were larger in size, had better contractility, were electrically more efficient,  exhibited  mature metabolic characteristics and had better-developed structures when compared to cells without  pIC.  

When they looked closely at what was going on inside the cells exposed to the compound, they found  that  pIC  had activated cellular programming that led to accelerated maturation. Specifically, it turned up the expression of the  JAG1  gene  ( which triggers a signaling pathway called Notch ),   and le d to  a host of epigenetic changes.  

The researchers also found that early cardiomyocytes exposed to  pIC  before implantation in mouse hearts matured faster than those not primed with the compound. They think   pIC  makes the cells more receptive to the maturation cues already  present.  

"There is some intrinsic clock  function  involved as well ,   which ,  in part ,   is  based on  epigenetic changes ," says Kamp. "It’s safe to say there is much more to learn that we don’t yet understand about cell autonomous developmental clocks."  

Developmental clocks, researchers think, dictate the amount of time it takes for a fertilized egg to develop  from a single immature cell  into a newborn  possessing all the specialized cells of the body. Despite being composed of the same cellular stuff, a baby mouse takes 21 days to develop, a human about 280 days, and an African elephant 600 days or more.   

Biermann’s finding, Kamp says, was a surprise, because no one has thought about using  pIC  or compounds like it  for this application.  It  also presents an opportunity to combine with other methods for accelerating maturation, and for doing so at a larger scale since  it can be easily added to and washed out of cells. But the finding is also not without caveats.  

"One obvious question is whether this is cardiomyocyte specific or if it could be useful in making neurons of pancreatic islet cells (defects in which can lead to diabetes ) ," says Kamp.  

He also points out that these accelerated cardiomyocytes are still not an exact match for adult heart muscle cells.  

"We are not at the promised land yet," he says. "We haven’t seen any aberrant effects, but we don’t know."   

Further, they don’t yet know how these cells will continue to age.   

"If we’re turning up the clock , are  they going to age faster, too?"  explain  Kamp.  "If we can get a better handle on it, it could be used for practical purposes and for better understanding developme nt. "    


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