A collection of cardioids
Researchers have worked for years to create organoids — miniature cellular structures that recapitulate features of larger organs — for nearly every organ in the body, in the hope that these tissue samples can serve as models in which to study everything from how diseases develop to which drugs could potentially work to combat a host of conditions.
In a new study published Thursday in Cell (and previously posted to the preprint server bioRxiv), researchers describe a new mini model of the heart, one they call a cardioid. In a departure from other efforts to recreate heart muscles and function in a dish, this latest attempt did not use external scaffolding around which heart cells organized themselves.
Instead, scientists relied on self-organization, in which stem cells that usually precede the creation of heart muscle were coaxed into becoming heart cells, also known as cardiomyocytes, with the help of six known signaling pathways.
To the scientists’ surprise, not only did this approach yield heart cells, but the cells organized themselves into a three-dimensional structure, complete with a single chamber reminiscent of a human heart (although a real one has four chambers) and a heartbeat that showed liquid being pumped around the chamber. The proof of concept came when the team injured these structures to mimic a heart attack: Cells tasked with repair migrated to the site of the injury to rebuild damaged tissue, much like what happens with full-fledged hearts.
What work preceded this?
What we did before was look into how you can efficiently differentiate stem cells to activate mesodermal lineages — heart cells, blood vessels, smooth vessel cells — to find out which signals differentiate them from stem cells. That was the groundwork for the work now.
Is this the first time your lab has done something like this?
This is the first major work as our lab started only about five years ago. And this has been the focus from the beginning. Previous approaches for the heart were mainly done using tissue engineering approaches, but ours is much more of a developmental approach that relies on self-organization of tissue.
Why not continue to use tissue engineering?
The engineering approach has the advantage that you can directly measure muscle strength and contraction and electrical activity — you can do those sorts of biophysical measurements.
The disadvantage is that you don’t get the same kind of physiology. Cells don’t like to be forced into something. Like with building a house or a piece of machinery, you need to have an exact plan for what needs to be built. If the concrete [or other material] doesn’t have the right specifications, or if one part is faulty, it won’t work as expected. And with an engineering approach, we won’t know how the biology of the heart works. You need to be able to recapitulate what actually happens in development and there are a lot of unknowns, so we can’t build it.
What was an advantage of not using engineering approaches?
What we also saw for the first time as a result was that when we injured them using cryoinjury — using a cold steel rod to injure the heart like in a heart attack. In heart attack, millions of cells die and the organ tries to somehow repair this damage. It starts secreting proteins to have cells migrate to the injured area. With engineering, you couldn’t see that. But in our case, we saw the response the way you might with a patient — cells known as cardio fibroblasts start to migrate towards the injured cells.
Beyond doing away with an engineering approach, what was another difference in what you did?
When we look at the protocol, we are the only lab that seems to have used all the signaling factors [for heart development]. Others leave some of them out because you can get cardiomyocytes without these other factors. They’re not important to just make the cells, but they are important for the structure of organs, including the lining and chamber on the inside.
Another advantage is that these structures are very reproducible and we can regenerate them and they all look the same. We can control the self-organization, like the size of the lumen of the cavity, for example.
Were you surprised at how this worked for you?
It was a bit of an accident — we wanted to figure out something else and started observing these structures that were beating and hollow. They were just freely floating in 96 well plates, and we were happy to see that. We expected that they would do something, but we didn’t expect this level of detail.
The next thing is that we are modeling genetic defects. This heart only had one cavity, but a real heart has more than one chamber, so we want to add the other chambers to communicate with each other [and figure out what’s happening]. We are also working on a regeneration model to help these cardiomyocytes to grow further [so that] when we injure them, they grow and heal each other.