During an average lifetime, a human heart beats two-and-a-half billion times. But how does it start, and what came first—the heart or the beating? Scientists think they put their finger on the first heartbeat, which occurs in the embryo long before there's anything that even remotely resembles the heart, as reported in the journal eLIFE. The study could have important implications for the field of regenerative medicine, and help scientists figure out how to build new hearts from scratch in the lab.
The heart is the first organ to form so that it can send oxygen and nutrients across a growing embryo. In the mouse, one week after fertilization, the heart starts off as a flat field of heart progenitor cells—immature cells that came from stem cells and which are gradually becoming real heart cells. Within the next 24 hours, the heart progenitors will come together to form a tube, which loops back onto itself to finally make a recognizable heart.
Previously it was thought that the beating started just as the heart tube was coming together. But now, scientists from the United Kingdom have pushed back the occurrence of the first heartbeat in mice by 12 hours, to a time when heart progenitors are scattered over a wide area.
Because mice develop faster than we do, this corresponds to roughly day 20 in human development in utero. By this time, the undeveloped foetus will have gone from being a single cell to a worm-like creature. It does not yet have arms or legs—not even a head, although the brain has started to form. But amazingly, it does have a heartbeat.
Stripped down to bare chemistry, heartbeats are bursts of calcium inside the heart muscle cells. As calcium levels rise and fall, they make the cells contract and relax, enabling the heart to work as a pump and move blood around the body.
To find the first heartbeat, the researchers made movies of mouse embryos as they developed in a dish, zooming in on the heart progenitor cells. By every measure, these cells are much too young to be called heart cells and lack the key machinery that turns calcium pulses into contractile force. Yet, surprisingly, when the researchers injected embryos with calcium that fluoresces, they could see flickering calcium waves—the beginnings of the heartbeat.
"We were surprised to find that calcium activity preceded the assembly of the machinery that does the contraction. You could imagine that the contraction machinery would have been in place first, waiting for the calcium signal to arrive, but in fact it was the other way around," said Shankar Srinivas, a professor of developmental biology at the University of Oxford, who co-led the study.
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These early calcium waves aren't just for show. They seem to be important for normal development, because blocking them by drugs messed up the cells' ability to become mature heart cells and form the heart.
It adds to an emerging theme in embryo research, where immature cells "grow up" by relying on molecular pathways previously thought to operate only in older cells, said Ian Scott, a senior scientist who studies heart development at the Hospital for Sick Children in Toronto. He was not involved in this study.
The calcium waves start off haphazardly in cells far apart, like lost fireflies. But then quickly—within a couple of hours—they come together to pulse in synchrony at a point when the beating becomes visible for the first time. Researchers want to find out how this switch occurs to be able to make functional heart tissue in the lab and to better understand heart disease.
"One of the major problems in regenerative medicine is how to make heart cells that beat in a coordinated manner. If we can understand how this occurs during development, it might help us engineer heart tissue with better synchrony," said Srinivas.
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