In 2014, I remarked here about in silico modeling for digital biology. The relationship
between AI-driven digital and in vitro modeling in systems biology is developing to
some extent in synch and in a mutually cross-fertilizing manner for the purpose
of minimizing both clinical and animal testing while expediting, improving and
reducing cost of biomedical innovation. Here is a sketch
of how this might work in a more organized fashion:
Organoids are artificial organ-like structures a few
millimeters in size bred in vitro that show realistic micro-anatomy. They are developed to perform medical
tests for which otherwise animal testing would have to be
used, that, ethical issues aside, is neither a very close nor highly reliable
approximation of human organs. Such partial models of the brain, heart or kidneys
have already been created in recent years for narrowly-tailored specific
purposes. Compared to in silico models,
they involve genuine human tissue and higher levels of complexity in some
respects.
Researchers working with Josef
Penninger
at the Institute of Molecular Biotechnology (IMBA) in Vienna,
Austria now report that they took a further step:
they established 3D tissue cultures that permit testing blood
vessels on the micro scale. Among additional future uses, their model presented
in Nature serves to simulate diabetic vascular damage.
Diabetics frequently
face vascular diseases as a consequence of their systemic condition. In the case of major blood vessels, potential
consequences include faster occurrences of atherosclerosis resulting in
myocardial infarction, stroke, and amputation of the lower limbs. However, diabetic
damage affecting small vessels, micro-vasculopathy, can have similarly catastrophic
results as it triggers diabetic kidney
disease that requires many diabetics to undergo
regular dialysis, and/or causes diabetic
retinopathy. Work on a 3D vascular organoid
model was finalized by a team of Reiner Wimmer,
who created 1-2-millimeter sized models of human capillaries, complete with endothelial
cells as a cavity lining layer as well as pericytes
as supporting cells.
To create a vascular model of capillaries,
the researchers induced human stem cells to differentiate into functional blood
vessels of a micro-format. These human blood vessel organoids were then
implanted into the kidneys of immunodeficient
mice that do not reject human cell tissue. The
organoids grew to form a stable, perfused vascular tree including arteries,
arterioles and venules. In 95 percent of cases, the organoids survived longer
than six months. This experimental design also appears to be well suited for
research on microvascular disease resulting from diabetes
mellitus type 2. In this type of microvascular
disease, one essential feature is the thickening and onion-like structure of
these vessels’ basement membrane and loss of vascular cells. The endothelial
cell layer “leaks,” and such leakage leads in diabetics to retinal disease that
causes a typical damage to the ocular fundus ending in blindness. Diabetes
impairs the functions of endothelial cells and disturbs communication between
the endothelium and pericytes.
The experiment imitated
type 2 diabetes in the lab by exposing the blood vessel organoids to hyperglycemia
by inducing high concentrations of sugar and inflammatory messengers
(cytokines), which in vitro induces thickening of the vascular basement
membrane. Down to the level of electron microscopy, all the typical
pathological changes to the capillaries became visible. The authors derived a first set of results from
tests in which the diabetic organoids were treated with a wide range of
conventional antidiabetic medications aimed at lowering blood sugar levels. None
of them showed any effect on the changes occurring in the vascular organoids. Perhaps
the best result came from an inhibitor of gamma-secretase enzyme (DAPT).
DAPT reduced the formation of vascular
thickening type IV collagen and normalized the emergence
of endothelial cells. According to the results of first impression, this is
apparently due to an effect attributed to the expression of the NOTCH3 gene.
Gamma-secretase
inhibitors have so far been tested as potential
Alzheimer drugs. This may yet prove important to future search for new
strategies for prevention and treatment of diabetic vascular disease.
The exciting part about this research
is that the authors were able to produce genuine human blood vessels out of
stem cells. These organoids show very high similarity to human capillaries, which
permits conducting meaningful studies of vascular diseases directly in live
human tissue. This study in experimental biology proved that organoids derived from human stem cells faithfully reproduce
the structure and function of human blood vessels and are useful systems for
modelling and identifying the regulators of diabetic vasculopathy, a
disease that affects hundreds of millions of patients worldwide. To the extent
the data from such models can be fed into AI to improve in silico modeling, a significant acceleration of pharmacological
testing cycles seems to be within reach.
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