When neurons perish, the brain cannot replace them. Most organs maintain stem cells to repair damage, but the few neural progenitors that remain in the adult brain have very limited potential to grow into different cell types, so they are unable to regenerate functional brain tissue that is lost to injury or disease.
To coax the brain into healing itself, researchers have searched high and low for methods that expand the brain’s progenitor cell population. In one approach, scientists isolate cells from different tissue sources and turn them into neural progenitor cells in vitro. The hope is that once transplanted into injured brain regions, these cells will integrate, survive, and restore brain function. This in vitro reprogramming method has shown promise, but can have severe drawbacks, including immune rejection and cancer risks.1,2
When Chun-Li Zhang started his laboratory at the University of Texas Southwestern Medical Center, he wanted to decipher how to activate the brain’s own self-healing program. In a recent study published in PNAS, Zhang showed that the transcription factor DLX2 can convert astrocytes into progenitors that produce various cell types, including neurons.3 These findings suggest that targeted DLX2 expression may one day help patients regenerate brain tissue.
Zhang studies astrocytes because they are the most common glial cell in the brain and because they are neurons’ next of kin. “During development, neural stem cells generate neurons first and later go on to produce astrocytes. So, they are from the same lineage. If you want to introduce a cell fate switch, the closer [related] the cells are, the easier,” Zhang said.
Neurons rely on other brain cells, such as glia, to function and survive. Therefore, when scientists screen for molecules with regenerative potential, they strive to identify those that convert brain cells into neural progenitor cells that generate multiple cell types. To identify such multipotent reprogramming factors, Zhang turned to a genetic tool called lineage tracing. Zhang generated several mouse models that express fluorescent reporters in neural progenitor cells and their progeny. This allowed the researchers to easily identify the progenitor’s daughter cells in brain tissues upon DLX2 overexpression, similar to spotting bright stars in a dark sky. “When we analyzed these [mice] at 12 weeks, we found that astrocytes can be reprogrammed to neurons, but we also found other cell types—astrocytes and oligodendrocytes—which was really interesting, and nobody has reported that before,” Zhang said.
“The in vivo work stands out; the rigor of using multiple mouse models combined with brain manipulations is very challenging from a technical perspective, but [because of this] the authors can say with confidence that they are targeting astrocytes,” said Kwanha Yu, assistant professor at Baylor College of Medicine’s Cell and Gene Therapy Center, who was not involved in the study.
Zhang next combined single cell sequencing with lineage tracing to molecularly characterize all of the converted astrocytes’ progeny and illuminate the reprogramming process. “We used a bioinformatic tool called pseudotime analysis and we could see that the astrocytes first become progenitor cells, progenitor cells become neuroblasts, then immature neurons, and then a small amount become mature neurons,” Zhang said.
“This is a powerful first step towards therapeutic intervention for brain damage induced by injury or neurodegenerative conditions,” said Yu, though he cautions that functional follow-up studies are needed to verify the newborn neurons’ behavior. Besides such studies, Zhang also plans to combine DLX2 with other cell fate determining factors to coax a progenitor cell into forming various neuronal subtypes. “Theoretically, if you reprogram only one astrocyte [into a progenitor], you can generate multiple neurons or astrocytes or oligodendrocytes through this expansion process,” Zhang said. The right reprogramming cocktail could help scientists convert the brain’s star-shaped glial cells into regenerative superstars that have the potential to mend the brain.
- F. Wang et al., “Reprogramming glial cells into functional neurons for neuro-regeneration: challenges and promise,” Neurosci Bull, 37(11):1625-36, 2021.
- W. Tai et al., “Regeneration through in vivo cell fate reprogramming for neural repair,” Front in Cell Neurosci, 14:107, 2020.
- Y. Zhang et al., “A single factor elicits multilineage reprogramming of astrocytes in the adult mouse striatum,” PNAS, 119(11):e2107339119, 2022.
- W. Niu et al., “In vivo reprogramming of astrocytes to neuroblasts in the adult brain,” Nat Cell Biol, 15(10):1164-75, 2013.
- W. Tai et al., “In vivo reprogramming of NG2 glia enables adult neurogenesis and functional recovery following spinal cord injury,” Cell Stem Cell, 28(5):923-937.e4, 2021.