Induced pluripotent stem cell modeling for hereditary cerebral small vessel disease

Cerebral small vessel disease targets the arterioles and capillaries,
with hereditary forms resulting from the pathological protein
expression of a single gene mutation. The neurovascular
unit is affected by such mutations, as its proper functioning
relies on complex bidirectional communication between neural
and vascular cell-types for blood-brain-barrier regulation. In
small vessel disease, the neurovascular unit depicts pathological
dysfunction of the blood-brain-barrier, cerebral blood-flow as
well as damage to the mechanical integrity of the microvessel
itself. Although the causal genetic mutations have been identified
in the literature, the processes that precipitate these hereditary
stroke and dementia syndromes have yet to be fully
uncovered. Induced pluripotent stem cells have exponentially
grown since their inception as a valuable cell-line which can be
easily sourced and differentiated into any somatic cell-type. In
vitro models have also recently risen to the forefront, attempting
to recreate biomimetic systems capable of recapitulating
disease mechanisms by stimulating cells to behave as they do
in vivo. These include 2D, 3D and dynamic disease models
that incorporate cutting-edge tissue engineering technology.
Furthermore, CRISPR/Cas9 gene editing can augment stem
cell modeling via fine manipulation of cell genotypes, allowing
for isogenic controls and even direct genetic manipulation
on diseased cells for phenotype-rescue. Induced pluripotent
stem cell-derived in vitro models have shown huge potential
in mimicking the in vivo environment and their continuous
advancement will lead to a greater understanding of both biomolecular
and physiological aspects of disease, with potential
future therapeutic interventions arising out of the knowledge
gained from their use.

Author(s): Amerikos Argyriou

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