Changes in neural progenitor lineage composition during astrocytic differentiation of human iPSCs
Summary
The regional specificity of stem cell-derived astrocytes is believed to be an important prerequisite for their application in disease modelling and cell-based therapies. Due to the lack of subtype-defining markers for astrocytes in different regions of the brain, the regional identity of in vitro-derived astrocytes is often declared by the dominant positional characteristics of their antecedent neural progenitors, patterned to a fate of interest, with the assumption that the positional trait is preserved by the derived astrocytes via linear descent. Using a human induced pluripotent stem cell line designed for tracing derivatives of LMX1A+ cells combined with a ventral midbrain induction paradigm, we show that astrocytes originating from LMX1A+ progenitors can only be generated if these progenitors are purified prior to the astrocyte differentiation process, or their progenies are gradually lost to progenies of LMX1A- progenitors. This finding indicates that the lineage composition of iPSC-derived astrocytes may not accurately recapitulate the founder progenitor population. Using deep single-cell RNA sequencing, we identified distinct transcriptomic signatures in astrocytes derived from the LMX1A+ progenitor cells. Our study highlights the need for rigorous characterization of pluripotent stem cell-derived regional astrocytes and provides a resource for assessing LMX1A+ ventral midbrain progenitor-derived human astrocytes. © 2024, Li et al.
| Authors | Li Z, Cardo LF, Rokicki M, Monzón-Sandoval J, Volpato V, Wessely F, Webber C, Li M |
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| Journal | eLife |
| Publication Date | 2025 Oct 28;13 |
| PubMed | 41150379 |
| PubMed Central | PMC12563561 |
| DOI | 10.7554/elife.96423 |