Individual variation in the emergence of anterior-to-posterior neural fates from human pluripotent stem cells

• Published in: Stem cell reports Vol. 19; no. 9; pp. 1336 - 1350
• Main Authors: Kim, Suel-Kee, Seo, Seungmae, Stein-O’Brien, Genevieve, Jaishankar, Amritha, Ogawa, Kazuya, Micali, Nicola, Luria, Victor, Karger, Amir, Wang, Yanhong, Kim, Hyojin, Hyde, Thomas M., Kleinman, Joel E., Voss, Ty, Fertig, Elana J., Shin, Joo-Heon, Bürli, Roland, Cross, Alan J., Brandon, Nicholas J., Weinberger, Daniel R., Chenoweth, Joshua G., Hoeppner, Daniel J., Sestan, Nenad, Colantuoni, Carlo, McKay, Ronald D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.09.2024; Elsevier
• Subjects: acid signaling; anterior or posterior neural fates; Cell Differentiation - genetics; Cell Line; cell line variation; Cell Lineage - genetics; early embryo; Epigenesis, Genetic; Gene Expression Regulation, Developmental; human population; Humans; pluripotent stem cells; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; retinoic; SOX21; Transcriptome; Tretinoin - metabolism; Tretinoin - pharmacology; pluripotent stem cells; early embryo; acid signaling; cell line variation; retinoic; human population; SOX21; anterior or posterior neural fates
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2024.07.004

Variability between human pluripotent stem cell (hPSC) lines remains a challenge and opportunity in biomedicine. In this study, hPSC lines from multiple donors were differentiated toward neuroectoderm and mesendoderm lineages. We revealed dynamic transcriptomic patterns that delineate the emergence of these lineages, which were conserved across lines, along with individual line-specific transcriptional signatures that were invariant throughout differentiation. These transcriptomic signatures predicted an antagonism between SOX21-driven forebrain fates and retinoic acid-induced hindbrain fates. Replicate lines and paired adult tissue demonstrated the stability of these line-specific transcriptomic traits. We show that this transcriptomic variation in lineage bias had both genetic and epigenetic origins, aligned with the anterior-to-posterior structure of early mammalian development, and was present across a large collection of hPSC lines. These findings contribute to developing systematic analyses of PSCs to define the origin and consequences of variation in the early events orchestrating individual human development. [Display omitted] •Cell imaging and transcriptomics reveal stable lineage bias across hPSC lines•Antagonism between SOX21 and RA signaling regulates regional neural lineage bias•Lineage biases are present in large collections of public hPSC lines•Lineage bias landscape across hPSC lines corresponds to mammalian development Variation in the lineage bias of pluripotent cells from different humans can be mapped onto the primary axes of in vivo mammalian development. This variation in cell potential is driven by stable, individual-specific transcriptomic signatures. These gene expression traits likely influence health, disease, and therapeutic responses throughout our lifetime.