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Refining and Defining the Optimal Recipe for Astrocytes to Neuron Conversion

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Review of “Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signaling Pathways” from Stem Cell Reports by Stuart P. Atkinson 

Following neuron loss, proliferative and reactive glial cells form the neural scar to protect neighboring tissues from further damage; however, these glial scars do suffer from a downside, as they also inhibit neuronal growth and synaptic transmission in the injured area [1]. The direct conversion of glia into neurons represents an exciting therapy for neuron loss and previous research from the laboratory of Gong Chen (Pennsylvania State University, University Park, PA, USA) demonstrated that the ectopic expression of the NEUROD1 neural transcription factor sufficed to transdifferentiate reactive astrocytes (a type of glial cell) into functional neurons in the mouse brain [2]. 

The subsequent development of this line of research recently culminated in the description of a defined cocktail of nine small molecules that reprogrammed human astrocytes into functional neurons [3]. While a small drug-driven protocol represents a clinically-applicable approach, the application of a large number of drugs, in a specific order, and for varying times remained as obstacles to efficient translation.

Now, the team returns with a new Stem Cell Reports study in which Yin et al. refine their chemical cocktail to four small molecule drugs and define the signaling pathways vital for the conversion of astrocytes into functional neurons in vitro and in vivo [4].

  • the authors identified four core small molecules that efficiently reprogrammed human astrocytes into functional neurons when applied at the same time
    • DAPT - a γ-secretase inhibitor that indirectly inhibits Notch
    • CHIR99021 - an aminopyrimidine derivative that potently inhibits glycogen synthase kinase 3β (GSK-3β)
    • SB-431542 - an inhibitor of the activin receptor-like kinase receptors, including the TGF-beta type I receptor
    • LDN193189 - a potent inhibitor of the bone morphogenetic (BMP) pathway
  • Chemically converted human neurons survived in vitro for several months and displayed heightened levels of functionality, as evidenced by the firing of repetitive action potentials and robust synaptic burst activities
    • In general, chemical conversion induced an upregulation in the expression of neural transcription factors (e.g., NEUROD1 and NGN2) and the downregulation of the REST neural suppressor gene
    • Cortical astrocyte-converted neurons mainly display glutamatergic characteristics, while midbrain astrocyte-converted neurons yield GABAergic neurons in addition to glutamatergic neurons
  • When applied in vivo through intracranial or intraperitoneal injection, the four-drug cocktail significantly increased adult mouse through neurogenesis 
    • These findings suggest that the identified core small drugs can pass through the blood-brain barrier to regulate adult neogenesis

While the authors highlight the development of this new “recipe” as a step closer to a potential drug therapy for neuroregeneration and brain repair, they also now want to develop their research further by refining and defining the optimal batch of small molecules that can produce higher levels of GABAergic neurons, and even dopaminergic neurons, and that can reprogram other glial cell populations present in the brain. However, the authors also note that challenges such as chemical toxicity and CNS drug delivery remain to be solved.

For more on the optimal means of converting astrocytes into neurons and more small molecule-based approaches to neuroregeneration and brain repair, stay tuned to the Stem Cells Portal!

References

  1. Yiu G and He Z, Glial inhibition of CNS axon regeneration. Nature Reviews Neuroscience 2006;7:617-27.
  2. Guo Z, Zhang L, Wu Z, et al., In Vivo Direct Reprogramming of Reactive Glial Cells into Functional Neurons after Brain Injury and in an Alzheimer’s Disease Model. Cell Stem Cell 2014;14:188-202.
  3. Zhang L, Yin J-C, Yeh H, et al., Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons. Cell Stem Cell 2015;17:735-747.
  4. Yin J-C, Zhang L, Ma N-X, et al., Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signaling Pathways. Stem Cell Reports 2019;12:488-501.