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Platelets by the Plateful?

13 February 2014 12:30 pm
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Go forth and clot. A megakaryocyte branches to form two platelets.

Dennis Kunkel, Microscopy Inc./Visuals Unlimited/Corbis

Go forth and clot. A megakaryocyte branches to form two platelets.

Platelets are the sand bags of the circulatory system, piling up in wounds to create clots and curb bleeding. Now, researchers in Japan have shown that they can grow large quantities of human platelets by starting with stem cells. Scaled up, the technique could provide a dependable source of replacement platelets for patients.

Platelets aren’t cells; they are shards of bone marrow cells called megakaryocytes. Cancer patients and people suffering from conditions such as aplastic anemia often don’t produce enough of these blood-clotters, so they can require supplementary infusions, sometimes more than once a week. Platelets gleaned from donated blood are the source for these transfusions, but they have several drawbacks that have spurred researchers to look for an alternative. Because the cell fragments can’t be refrigerated—low temperatures damage them—their shelf life is only a few days, versus weeks for red blood cells, and platelets are more likely to be tainted with dangerous bacteria. Vascular biologist Denisa Wagner of Harvard Medical School in Boston points out another motivation to identify new platelet sources: the aging of the world’s population. Older folks are more likely to require transfusions because they naturally produce fewer platelets, she notes.

In recent years, two teams reported that they had reared human megakaryocytes and platelets from embryonic stem cells and so-called induced pluripotent stem (iPS) cells, adult cells that have reverted to stem cells. However, neither technique furnished enough platelets for a transfusion. To increase efficiency, Koji Eto of Kyoto University in Japan, who led one of the teams, and colleagues refined their recipe. By prodding human iPS cells and embryonic stem cells with drugs, they cranked up the activity of three genes that prompt the cells to divide and prevent them from committing suicide. This step yielded megakaryocyte precursors, cells that can give rise to megakaryocytes. The team found that the megakaryocyte precursors could survive and continue dividing in culture for more than 5 months, even after being frozen and thawed.

When the researchers switched off the three genes by withdrawing the drugs, the cells matured into megakaryocytes and began pumping out platelets. Online today in Cell Stem Cell, Eto and colleagues estimated that within 5 days the method could produce enough platelets for a transfusion. To test the platelets’ clotting capabilities, the researchers injected them into mice that had blood vessel injuries. The lab-made platelets formed clots in the animals, the researchers showed.

To use this strategy medically, Eto envisions that the megakaryocyte precursors would be kept frozen. When needed, they could be thawed and coaxed to specialize into platelet-makers. Although the megakaryocytes induced by the team weren’t as productive as those in the bone marrow, growing the cells on a large scale could make up for this inefficiency and allow generation of ample amounts of platelets, he adds. Eto says he expects to begin clinical trials of lab-produced platelets in 2 or 3 years.

Other researchers agree that this study brings the field nearer the goal of deriving usable platelets from stem cells. “I was very impressed,” says stem cell biologist Nicolas Pineault of Canadian Blood Services in Ottawa. “I think it’s very close” to being practical for humans, Wagner says.

The quality of the lab-made platelets could be a sticking point, though. For example, they aren’t as clingy as platelets born in the bone marrow, which might limit their clotting ability. “They are good platelets, but they are not excellent platelets,” Pineault says. The researchers still have a lot of work to do before the lab-grown platelets can substitute for donor-derived ones, adds hematologist Mortimer Poncz of the University of Pennsylvania Perelman School of Medicine. “Are we there yet? No.”

Molecular geneticist Benjamin Kile of the Walter and Eliza Hall Institute of Medical Research in Australia acknowledges that many questions remain about the lab-made platelets, including their clotting capacity and life span in humans. But he says that Eto and colleagues deserve credit for showing that it’s possible to produce copious amounts of the cell fragments. “You can’t do clinical trials until you’ve managed to grow enough platelets,” he says.

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