Combining single-cell tracking and omics improves blood stem cell fate regulator identification

• Published in: Blood 2022-09, Vol.140 (13), p.1482-1495
• Main Authors: Wehling, A., Loeffler, D., Zhang, Y., Kull, T., Donato, C., Szczerba, B., Camargo Ortega, G., Lee, M., Moor, A., Göttgens, B., Aceto, N., Schroeder, T.
• Format: Article
• Language: English
• Subjects: Cell Differentiation; Cell Division; Cell Tracking; Hematopoiesis and Stem Cells; Stem Cells
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022016880

Molecular programs initiating cell fate divergence (CFD) are difficult to identify. Current approaches usually compare cells long after CFD initiation, therefore missing molecular changes at its start. Ideally, single cells that differ in their CFD molecular program but are otherwise identical are compared early in CFD. This is possible in diverging sister cells, which were identical until their mother's division and thus differ mainly in CFD properties. In asymmetrically dividing cells, divergent daughter fates are prospectively committed during division, and diverging sisters can thus be identified at the start of CFD. Using asymmetrically dividing blood stem cells, we developed a pipeline (ie, trackSeq) for imaging, tracking, isolating, and transcriptome sequencing of single cells. Their identities, kinship, and histories are maintained throughout, massively improving molecular noise filtering and candidate identification. In addition to many identified blood stem CFD regulators, we offer here this pipeline for use in CFDs other than asymmetric division. •Integrating single-cell omics with tracking and dynamics quantification to compare HSC daughter cells improves fate regulator detection.•Transcriptome divergence at HSC activation after asymmetric division includes differential cell cycle and adhesion regulation. [Display omitted]