genome and could ultimately add a new dimension to modeling and understanding human
disease using iN cells. For neuroscientists in particular, generation of an unlimited supply of human
neuronal cells (neurons are notoriously difficult to
obtain from patients and cannot be expanded in
culture) was merely an ambition, far from reality
until this opportunity emerged a few years ago.
It is now possible to design clinical trials in the
dish that may revolutionize preclinical screening
of therapeutic compounds by testing them in a
high-throughput manner on human neuronal cells,
in parallel to mouse modeling.
One application of direct lineage reprogramming in the nervous system is the generation of
new neurons in situ by the direct conversion of
cells that are resident within the central nervous
system. Given the highly specialized nature of
neurons and the complexity of the connections
they make and receive, it may be advantageous
to generate new neurons by direct conversion of
other classes of neurons. The starting neurons
may have already acquired basic pan-neuronal
features that are functionally critical. However, a
major challenge will be to identify and overcome barriers that currently hamper reprogramming of neurons in the adult nervous system.
The mechanisms that maintain neuronal class–
specific identity throughout the life span of an
organism are largely unknown. Although it is
speculative at this stage, we propose that neurons might maintain their identity using unique
mechanisms. It is intriguing that the closure of
the temporal window of nuclear plasticity of neurons loosely corresponds to their integration into
circuit. This suggests the provocative possibility
that elements of neuronal identity are sustained
by the network in which each neuron integrates.
It remains to be determined whether and how
local (or even long-distance) circuitry would react
in response to a change in neuronal class–specific
identity induced by reprogramming. Should adult
neuronal reprogramming become a reality, this in
vivo application could be informative in elucidating aspects of circuit plasticity and understanding
some of the rules that shape circuit maintenance
in vivo. With the knowledge of development and
cell identity of all neurons present in the nervous
system of Caenorhabditis elegans, this organism
may be a perfect first model system to determine
whether circuit remodeling accompanies the
process of direct reprogramming in vivo. Investigation of invertebrate organisms that are endowed with natural reprogramming capabilities
will also facilitate understanding of reprogramming in mammals.
As evidenced by the presentation of the Nobel
Prize in 2012, nuclear reprogramming is an ex-
citing, rapidly growing field with the potential to
transform basic science and clinical research.
Direct reprogramming from one cell into another
may be particularly advantageous for the central
nervous system because of its in vivo applica-
bility, in addition to neuronal production in the
dish. Although the progress in the field has gen-
erated as many unresolved questions as answers,
direct reprogramming has shown promise to rev-
olutionize the way the field thinks about neuro-
nal stability and repair.
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