A single factor elicits multilineage reprogramming of astrocytes in the adult mouse striatum

Proc Natl Acad Sci U S A. 2022 Mar 15;119(11):e2107339119. doi: 10.1073/pnas.2107339119. Epub 2022 Mar 7.

Abstract

SignificanceOutside the neurogenic niches, the adult brain lacks multipotent progenitor cells. In this study, we performed a series of in vivo screens and reveal that a single factor can induce resident brain astrocytes to become induced neural progenitor cells (iNPCs), which then generate neurons, astrocytes, and oligodendrocytes. Such a conclusion is supported by single-cell RNA sequencing and multiple lineage-tracing experiments. Our discovery of iNPCs is fundamentally important for regenerative medicine since neural injuries or degeneration often lead to loss/dysfunction of all three neural lineages. Our findings also provide insights into cell plasticity in the adult mammalian brain, which has largely lost the regenerative capacity.

Keywords: DLX2; astrocytes; induced neural progenitor cells; in vivo reprogramming; scRNA-seq.

MeSH terms

  • Animals
  • Astrocytes / cytology*
  • Astrocytes / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Differentiation* / genetics
  • Cell Lineage* / genetics
  • Cellular Reprogramming* / genetics
  • Corpus Striatum / cytology*
  • Corpus Striatum / metabolism
  • Fluorescent Antibody Technique
  • GABAergic Neurons / cytology
  • GABAergic Neurons / metabolism
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Genes, Reporter
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Mice
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / metabolism
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neurogenesis
  • RNA-Seq
  • Receptors, Notch / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Bcl11b protein, mouse
  • Distal-less homeobox proteins
  • Homeodomain Proteins
  • Receptors, Notch
  • Repressor Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins