Real brain have vasculature. Studying the vasculature and neural cells when is important because it delivers
oxygen, glucose and medicine to brain cells, and also because research
shows that in strokes, Alzheimer's disease and brain injury, the brain
sometimes attempts to redesign its vasculature to compensate for what's
happening to it.
A wondrous variety of mini-brains -
3-D cultures of neural cells that model basic properties of living
brains - has been made by scientists. But, a new finding could add to the field's growing excitement
in an entirely new "vein": Brown University's mini-brains now grow blood
‘With lab developed mini-brains that have the potential to develop blood vessels, researchers can study a range of injury conditions, drugs that are being tested and conditions - such as stroke and diabetes - together.’
The networks of capillaries within the little balls of nervous
system cells could enable new kinds of large-scale lab investigations
into diseases, such as stroke or concussion, where the interaction
between the brain and its circulatory system is paramount, said Diane
Hoffman-Kim, senior author of the study in The Journal of Neuroscience Methods
. More fundamentally, vasculature makes mini-brains more realistic models of natural noggins.
"This is exciting because real brains have vasculature," said
Hoffman-Kim, an associate professor of medical science and of
engineering at Brown. "We rely on it. For our neurons to do their thing,
they have to be close to some blood vessels. If we are going to study
lab models of the brain, we would love for them to have vasculature,
Making the most of mini-brains
Especially because scientists can make them by the hundreds,
mini-brains hold promise not only for advancing medical and scientific
research, but also for doing so with less need for animal models.
Hoffman-Kim's lab first described its mini-brain method in 2015. While
the engineered tissues appeared relatively simple compared to some
others, they were also relatively easy and inexpensive to make.
But what had remained unnoticed at the time, even by the inventors,
was that the little 8,000-cell spheres cultured from mouse cells were
capable of growing an elementary circulatory system.
Only as members of the lab including lead author and Brown Graduate
School alumna Molly Boutin continued to work with and study the
mini-brains did they discover that after about day three of culture,
about two-thirds of the mini-brains had grown networks of non-neural
tissue. Closer inspection revealed that these tangles of spaghetti were
self-assembled (i.e. they just grew) tubes made of the cells and
proteins found in blood vessels.
The new study features a wide variety of imaging experiments in
which staining and fluorescence techniques reveal those different cell
types and proteins within the mini-brain spheres. The study also
documents their integration with the neural tissues. Cross-sections
under a transmission electron microscope, meanwhile, show that the
capillaries are indeed hollow tubes that could transport blood.
Of course, there is no blood in a tiny mini-brain, Hoffman-Kim said.
They exist in an agarose wellplate, not in a living animal. But she's
currently working with a colleague at Brown to design a way to connect
the mini-brains with a microfluidic apparatus that could produce an
external source of circulation through a mini-brain.
"We've sketched on a few napkins together," she quipped.
The capillary networks are not as dense as they would be in a real
brain, she acknowledged. The study also shows that they don't last
longer than about a week or two.
Aware of both their constraints and their potential, Hoffman-Kim's
lab has already started experiments to take advantage of the presence of
vasculature. Study second author Liana Kramer, a Brown senior, has
begun looking at what happens to the vasculature and neural cells when
mini-brains are deprived of oxygen or glucose. Later that same test bed
could be used to examine the difference that different drugs or other
"We can study a range of injury conditions, several drugs that are
being tested and several conditions - such as stroke and diabetes -
together," Hoffman-Kim said.