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Direct neuronal reprogramming by temporal identity factors.

Camille Boudreau-Pinsonneault1,2, Luke Ajay David1,2, José Alex Lourenço Fernandes3,4

  • 1Cellular Neurobiology Research Unit, Montreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada.

Proceedings of the National Academy of Sciences of the United States of America
|May 1, 2023
PubMed
Summary
This summary is machine-generated.

Early temporal identity factors, Ikzf1 and Ikzf4, can reprogram mature mouse Müller glial cells into new cells resembling neurons. This discovery reveals a general mechanism for neuronal reprogramming in differentiated cells.

Keywords:
cell therapyregenerationreprogrammingretinatranscription factors

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Cell Biology

Background:

  • Terminally differentiated cells typically have limited plasticity.
  • Temporal identity factors are known to reprogram neural progenitors but their effect on differentiated cells is unknown.

Purpose of the Study:

  • To investigate if temporal identity factors can reprogram terminally differentiated cells.
  • To identify specific factors capable of inducing cell fate changes in mature retinal cells.

Main Methods:

  • Developed a conditional gene expression system for screening reprogramming factors in mouse retinal glial cells.
  • Employed genetic lineage tracing, histology, immunohistochemistry, and single-cell multiomics analyses.
  • Utilized mouse embryonic fibroblasts for in vitro reprogramming experiments.

Main Results:

  • Coexpression of Ikzf1 and Ikzf4 directly converted Müller glial cells into induced ONL (iONL) cells.
  • iONL cells exhibited molecular characteristics of bipolar cells, with some expressing a cone photoreceptor marker.
  • Ikzf1 and Ikzf4 reprogrammed mouse embryonic fibroblasts into induced neurons by altering chromatin and gene expression.

Conclusions:

  • Temporal identity factors Ikzf1 and Ikzf4 possess general neuronal reprogramming capabilities in terminally differentiated cells.
  • This study uncovers a novel method for generating neuronal cell types from non-neuronal or less differentiated cells.