By tweaking a single gene, a group of scientists from UT Southwestern in Dallas reprogramed nervous system support cells called astrocytes in the spinal cords of living mice to become new nerve cells. This research, reported this week in Nature Communications
, opens the tantalizing possibility that spinal cord cell replacement and repair might be accomplished not by transplanting outside stem cells but by manipulating existing cells to take on new identities.
The research team, led by molecular biologist Chun-Li Zhang, Ph.D., reported last fall in Nature Cell Biology
that they had successfully turned mouse brain astrocytes into neurons, and that these new cells formed networks.
From a UT press release:
"Our earlier work was the first to clearly show in vivo (in a living animal) that mature astrocytes can be reprogrammed to become functional neurons without the need of cell transplantation. The current study did something similar in the spine, turning scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons," said Dr. Zhang.
"Astrocytes are abundant and widely distributed both in the brain and in the spinal cord. In response to injury, these cells proliferate and contribute to scar formation. Once a scar has formed, it seals the injured area and creates a mechanical and biochemical barrier to neural regeneration," Dr. Zhang explained. "Our results indicate that the astrocytes may be ideal targets for in vivo reprogramming."
From the published abstract:
Here we show that resident astrocytes can be converted to doublecortin (DCX)-positive neuroblasts by a single transcription factor, SOX2, in the injured adult spinal cord. Importantly, these induced neuroblasts can mature into synapse-forming neurons in vivo. Neuronal maturation is further promoted by treatment with a histone deacetylase inhibitor, valproic acid (VPA). The results of this study indicate that in situ reprogramming of endogenous astrocytes to neurons might be a potential strategy for cellular regeneration after SCI.
Here’s what they did: The scientists used virus vectors to introduce 12 types of transcription factors -- gene regulator molecules -- into the spinal cords of mice with paralyzing injuries. Of the 12, only SOX2 was able to transform fully differentiated, adult astrocytes to an earlier neuronal precursor, or neuroblast, stage of development, Dr. Zhang said.
SOX2 is a well known gene factor: It is one of the four transcription factors used in the groundbreaking experiments
to create stem cells by reverse programming skin cells to become very much like embryonic stem cells. This process, induced pluripotent stem cell (iPSC) generation, won the 2012 Nobel Prize for Japanese researcher Shinya Yamanaka.
In the current study, the researchers also gave the mice valproic acid (VPA), a drug that helps the neuroblasts survive and differentiate into neurons. VPA has been long been used to treat epilepsy, bipolar disorder, and migraine headaches, according to Dr. Zhang.
So, did the formation of new neurons help spinal cord injured mice? No. Zhang said the paper proves they can make neurons but that the process is not yet efficient. Only a small percentage of astrocytes made the switch to become neuroblasts – not enough to affect recovery or even to measure with electrophysiology. “It’s just a proof of principle,” said Zhang. “We got some cells, but we’re not getting the number we really want for repair. We’re working at full force to boost the efficiency. Then we can do recordings to see if they have electrical properties.”
From the release:
The current study reports neurogenesis (neuron creation) occurred in the spinal cords of both adult and aged (over one-year old) mice of both sexes, although the response was much weaker in the aged mice, Dr. Zhang said. Researchers now are searching for ways to boost the number and speed of neuron creation. Neuroblasts took four weeks to form and eight weeks to mature into neurons, slower than neurogenesis reported in lab dish experiments, so researchers plan to conduct experiments to determine if the slower pace helps the newly generated neurons properly integrate into their environment.