Scientists Create World's First 3D-Printed Heart Using Patient's Own Cells
Researchers at Tel Aviv University have successfully printed the
world’s first 3D heart using a patient’s own cells and biological
materials to “completely match the immunological, cellular, biochemical,
and anatomical properties of the patient.”
Until now, researchers have only been able to 3D-print simple tissues lacking blood vessels. "This heart is made from human cells and patient-specific biological
materials. In our process these materials serve as the bioinks,
substances made of sugars and proteins that can be used for 3D printing
of complex tissue models," said lead researcher in a statement.
"People have managed to 3D-print the structure of a heart in the past,
but not with cells or with blood vessels. Our results demonstrate the
potential of our approach for engineering personalized tissue and organ
replacement in the future." F,
G) A printed heart within a support bath. H) After extraction, the left
and right ventricles were injected with red and blue dyes,
respectively, in order to demonstrate hollow chambers and the septum
in‐between them. Describing their work, the research team started by taking biopsies of fatty tissues from abdominal structures known as the omentum in
both humans and pigs. The tissue's cellular materials were separated
from those that weren’t and reprogrammed to become pluripotent stem
cells, “master cells”
able to make cells from all three body layers with the potential to
produce any cell or tissue in the body. The team then made the extracellular matrix
– made up of collagen and glycoproteins – into a hydrogel used as the
printing “ink”. Cells were mixed with the hydrogel and then
differentiated into cardiac or endothelial cells (those that line the
interior surface of blood and lymphatic vessels) to create
patient-specific, immune-compatible cardiac patches complete with blood
vessels and, ultimately, an entire heart bioengineered from “native”
patient-specific materials.
Though promising, the team is quick to remind us that their hearts are not yet ready for human transplantation.
"At this stage, our 3D heart is small, the size of a rabbit's heart,"
said the researcher. "But larger human hearts require the same technology."
For starters, creating a human heart would take much longer and
require billions of cells – not just millions. Furthermore, the
cherry-sized hearts don’t necessarily behave like hearts, requiring
researchers to further develop and “train” them to be like human hearts
and form a pumping ability. Currently, the cells can contract but do not
work together.
Regardless, the development is a massive step for the advancement of organ transplantation. Heart disease is the leading cause of death in men and women in the US, with heart transplants being the only
treatment available to those with end-stage heart failure. Not only does
a shortage of donors require the development of new strategies, but
creating hearts that jive with a patient’s unique biological makeup
could prevent the risk of rejection.
"The biocompatibility of engineered materials is crucial to
eliminating the risk of implant rejection, which jeopardizes the success
of such treatments," said the researcher. "Ideally, the biomaterial should
possess the same biochemical, mechanical and topographical properties of
the patient's own tissues. Here, we can report a simple approach to
3D-printed thick, vascularized and perfusable cardiac tissues that
completely match the immunological, cellular, biochemical and anatomical
properties of the patient." After “training” the hearts to efficiently pump, the team hopes to transplant them into animals for further testing. Cells
from a patient's omentum tissue are separated and processed into a
personalized thermoresponsive hydrogel. The cells are reprogrammed to
become pluripotent and are then differentiated to cardiomyocytes and
endothelial cells before encapsulation within the hydrogel to generate
the bioinks used for printing. The bioinks are then printed to engineer
vascularized patches and complex cellularized structures.
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Scientists
are close to gaining the ability to grow full-sized, beating human
hearts from stem cells, which is fantastic news for the thousands of
people around the world who are waiting patiently for a heart
transplant. In the United States alone,
there are currently some 4,000 people waiting for a heart transplant,
but only some 2,500 of them will actually receive one in the next year.
In addition, there’s the substantial risk of the heart being rejected by
the patient’s body during the transplant due to the reaction against
foreign cells. As a result, researchers have
been hard at work creating synthetic organs from the patients’ very own
cells. A team of scientists is a step closer to its goal, thanks to using
adult skin cells to regenerate functional human heart tissue. The scientists haven’t quite
reached the point of growing working hearts from patients’ own tissues,
and that’s because organs have a particular architecture that needs to
be adhered to. It’s relatively easy to do this in a laboratory using a
scaffolding on which the cells can build – think of it as building a
house with the frame already constructed. Previously, the scientists
managed to create a technique using a detergent solution to strip a
donor organ of cells that might set off an immune response in the
patient receiving a new heart. They tried the experiment on mice
initially but then attempted to replicate their findings on human
hearts. Cells were stripped away from
some 73 hearts that were deemed unfit for transplantation, then the
researchers took adult skin cells and used a new technique with
messenger RNA to turn them into pluripotent stem cells, the cells that
can become specialized to any type of cell in the human body, and then
induced them to become two different types of cardiac cells. The next step involved ensuring
that the remaining matrix would provide a strong foundation for new
cells so that the induced cells could be placed into them. They infused
the hearts with a nutrient solution for the next two weeks and allowed
them to grow under similar forces that they would be exposed to inside
the human body. After the two weeks were up, the
researchers observed that the synthetic hearts looked similar to
immature natural hearts, and they even started beating when they gave
them a shock of electricity. This study isn’t the first time
that heart tissue has been grown in a lab, but it’s the closest that
researchers have ever come to their end goal, which is to grow an entire
working human heart. The next step toward growing a whole heart would
be to improve their yield of pluripotent stem cells, as well as finding a
way to help said cells mature much more quickly. The ultimate goal is
to be able to create tailor-made hearts for patients that need them,
thus negating the risks associated with transplant rejection.
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Alzheimer's disease has a range of risk factors, but one of the clearest connections is the gene apoE4.
Now, researchers have peered closer at the
protein encoded by this gene and uncovered how it affects the brain, how
it increases the risks of Alzheimer's and most importantly, how the
damage can be reversed.
The apoE gene
comes in three variations, apoE2, E3 and E4, and everybody carries two
copies in various combinations. The most common form is apoE3, and it
doesn't seem to have any influence over a person's likelihood of
developing Alzheimer's. But apoE4, present in up to 15 percent of
people, is the real troublemaker: Having one copy increases the
Alzheimer's risk by two to three times, while those unlucky enough to
have two copies are 12 times more likely to develop the disease.
But why is that the case? The
proteins created by these genes are extremely similar, with apoE4
differing from apoE3 at only one tiny point. So, the new study set out
to examine what problems the former is causing in the brain, and whether
that single change can be canceled out.
Rather than using mouse
models, the results of which don't usually translate well to human
biology, the researchers experimented with human cells
instead. The team gathered skin cells from Alzheimer's patients with two
apoE4 genes, as well as some from people with two apoE3 genes without
Alzheimer's. These were converted into induced pluripotent stem cells,
and then turned into human neurons.
The team compared the
neurons from the apoE3 and apoE4 donors, and found that the latter
didn't function as well as they should. This means the protein breaks
down into fragments in the cells, over time leading to the build-up of
proteins in the brain that forms the calling card of Alzheimer's.
Interestingly, apoE4's
devastating effects are clear in humans but not in mice. That
illustrates the flaws in using animal models of human diseases, and may
go a long way towards explaining why treatments that previously seemed
so promising in mice haven't panned out in human trials.
"There's an important species
difference in the effect of apoE4 on amyloid beta," says the first author of the study. "Increased amyloid beta production is
not seen in mouse neurons and could potentially explain some of the
discrepancies between mice and humans regarding drug efficacy. This will
be very important information for future drug development."
Having determined that
apoE4 damages human brain cells, the team wanted to examine the root of
the problem – namely, whether the problems were caused by the presence
of apoE4 or perhaps just the absence of apoE3.
"It's
fundamentally important to address this question because it changes how
you treat the problem," says the lead author of the study.
"If the damage is caused due to the loss of a protein's function, you
would want to increase protein levels to supplement those functions. But
if the accumulation of a protein leads to a toxic function, you want to
lower production of the protein to block its detrimental effect."
To figure that out, the team
grew brain cells with no forms of apoE, and found they functioned much
the same as those with the common apoE3 protein. As soon as apoE4 was
added though, the neurons degraded in a familiar Alzheimer's fashion,
indicating that this protein is actively the problem.
Best of all, the researchers
were able to fix the damage after the fact, using a class of compounds
that turn apoE4 into something closer to E3. Treating the brain cells
with these structure-correcting molecules restored function to the
neurons, and effectively reversed the signs of Alzheimer's. The
scientists are now looking to the pharmaceutical industry to help with
improving the compounds for future testing in human patients.
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The first functional 3D human stomach tissue in a laboratory has been grown by scientists using pluripotent stem cells.
Scientists at Cincinnati Children's Hospital Medical Center used human
pluripotent stem cells, which can become any cell type in the body, to
grow a miniature version of the stomach.
In collaboration with
researchers at the University of Cincinnati College of Medicine, they
used laboratory generated mini-stomachs to study infection by H pylori
bacteria, a major cause of peptic ulcer and stomach cancer.
This first-time molecular generation of 3D human gastric organoids
presents new opportunities for drug discovery and studying some of the
underpinnings of obesity related diabetes, according to Jim Wells,
principal investigator.
It also is the first time researchers
have produced 3D human embryonic foregut — a promising starting point
for generating other foregut organ tissues like the lungs and pancreas,
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Scientists have created a new type of human stem cell in the lab which
they believe will be better at making replacement organs than existing
stem cells.
In theory stem cells can develop into any kind of cell, so they
could be used to repair damaged organs or even build them from scratch.
But most stem cells are not that flexible, researchers said.
The best ones are "pluripotent", meaning they can turn into
anything. Such cells have to be taken from embryos or made by reverting
adult cells to their embryonic state, called induced pluripotent stem
cells, 'New Scientist' reported.
But these pluripotent stem cells still carry genetic baggage from their previous existence.
"This [baggage] has been one of the confounding problems in
this area," said Austin Smith of the University of Cambridge, who led
the team that developed the new cells.
The new cells have had their cellular memories wiped clean.
Their genes have been cleansed of most methylation markers, so they
behave more predictably and transform more consistently into other
tissues.
The team hopes that this will make them a better building block for organs and tissues than existing embryonic stem cells.
"Nothing has been written or drawn on them to tell them what to
do or become. These cells could be a better and more pristine starting
point," said Smith.
Called naive stem cells, these have long been known in mice and rats, but they have never been found in humans.
To make them, Smith and his colleagues mimicked the process that creates their mouse counterparts.
They gave human embryonic stem cells extra copies of two genes,
Nanog and Klf2, which triggered the gene network needed to make the
naive cells.
To confirm that the cells were naive stem cells, the team tracked which other genes were switched on.
Two genes called Klf4 and Tfcp2l1, which are active in mouse naive stem cells, were switched on in the human naive cells.
When the team examined human embryos at around 7 days old they found the genes were active, said Smith.
This suggests naive stem cells exist in natural human embryos.
In mouse embryos, 10 to 20 naive stem cells appear just before the
embryos implant into the uterus, Smith said, adding that the human naive
cells may appear at the same time.
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