Changes in neural progenitor lineage composition during astrocytic differentiation of human iPSCs

Li, Zongze ORCID: https://orcid.org/0000-0002-9923-7205, Cardo, Lucia Fernandez, Rokicki, Michal, Monzon Sandoval, Jimena, Volpato, Viola, Wessely, Frank, Webber, Caleb ORCID: https://orcid.org/0000-0001-8063-7674 and Li, Meng ORCID: https://orcid.org/0000-0002-4803-4643 2025. Changes in neural progenitor lineage composition during astrocytic differentiation of human iPSCs. eLife 13 , RP96423. 10.7554/eLife.96423.3

PDF - Published Version Available under License Creative Commons Attribution. Download (13MB)

Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine ?? NMHII ??
Publisher:	eLife Sciences Publications
Date of First Compliant Deposit:	3 November 2025
Last Modified:	03 Nov 2025 14:35
URI:	https://orca.cardiff.ac.uk/id/eprint/182063

Actions (repository staff only)

Edit Item