It’s really difficult to convince a mature brain to grow new neurons. Brains tightly control
that sort of regulatory function. This difficulty is one of the reasons
that prognoses for brain injuries or degenerative brain diseases are so
scary; outside the hippocampus or olfactory bulb, once a neuron is
gone, its place in the connectome is
empty. Treatment options for neurodegenerative diseases or traumatic
brain injuries (TBI) are few and unsatisfying. Brains can’t be
chemically induced to grow new neurons to replace the old ones.
Introducing individual stem cells or neurons in solution doesn’t work:
the specific adhesive and signaling connections between neurons are so
important that when disrupted by a or stroke, the network can’t recover
healthy function faster than its constituent cells die off. Some neurons
are stuck together by transmembrane proteins, which means that they
can’t be separated without damage, even for transplant.
Transplanted neurons displaying electrical activity. Image credit: Prabhas Moghe, Rutgers via NIH News
In light of restrictions like these, scientists wondered
whether they might not get better results by introducing intact networks
of neurons into damaged brains, rather than individual neurons in
isolation. To answer that question, a team led by scientists from
Rutgers University created a 3D micro-scaffold, electrospun from polymer
fibers and small enough to pass through a standard hypodermic needle,
on which they grew neurons before injecting them into brains – where the
neuron transplants began to take hold and flourish.
The researchers first cultured human neurons by converting
mature adult cells like skin cells back into pluripotent stem cells,
then chemically inducing their development into neurons. Then they
seeded the new neurons into the fibrous 3D polymer scaffold. To explore
the reasons that this technique might succeed or fail, the researchers
experimented by varying the thickness of the fibers they used to
construct the scaffold, and the distance between them. Thicker fibers
ended up performing the best, lending credence to the idea that neurons
need to be close enough that they can link up with other nearby neurons,
but not crammed in so close that there’s no room for synapses to form
and change. “If the scaffolds were too dense, the stem cell-derived
neurons were unable to integrate into the scaffold, whereas if they are
too sparse then the network organization tends to be poor,” explains Prabhas Moghe, Ph.D., co-senior author of the paper.
After keeping the cells in culture for a few weeks, the
scientists observed the development of small neuronal networks within
the polymer scaffold — networks that the team went on to inject directly
into slices of mouse brain, but also into the striatum of the brains of
living mice. The researchers found that the scaffolded, interconnected
neurons survived much better than individual neurons when injected into
the mouse brains, on the order of a 40-fold improvement. Furthermore,
the scaffolded neurons exhibited electrical activity and better
outgrowth in the mouse brains, and once they were ensconced the
transplanted neurons began to express proteins important to the
formation of synapses – a solid indication that the transplanted cells
could integrate themselves into the host brain tissue.
The authors have a clear vision of what they want to do with
this technology. Their goal is to develop methods to induce stem cells
to differentiate into excitatory dopaminergic neurons: the type of
neuron that degenerates in people with Parkinson’s disease. The
supporting work will involve fine-tuning the materials and behavior of
these micro-scaffolds to better safeguard the development of
dopamine-producing neurons, and finding the best mouse models of the
disease to test their transplant therapy.
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