Tracking the gene expression programs and clonal relationships that underlie mast, myeloid, and T lineage specification from stem cells
T cells develop from hematopoietic progenitors in the thymus and protect against pathogens and cancer. However, the emergence of human T cell-competent blood progenitors and their subsequent specification to the T lineage have been challenging to capture in real time. Here, we leveraged a pluripotent stem cell differentiation system to understand the transcriptional dynamics and cell fate restriction events that underlie this critical developmental process. Time-resolved single-cell RNA sequencing revealed that downregulation of the multipotent hematopoietic program, upregulation of >90 lineage-associated transcription factors, and cell-cycle exit all occur within a highly coordinated developmental window. Gene-regulatory network inference uncovered a role for YBX1 in T lineage specification. We mapped the differentiation cell fate hierarchy using transcribed lineage barcoding and discovered that mast and myeloid potential bifurcate from each other early in hematopoiesis, upstream of T lineage restriction. Our systems-level analyses provide a quantitative, time-resolved model of human T cell fate specification. A record of this paper's transparent peer review process is included in the supplemental information.
Authors
- Aden Forrow
- Yale S. Michaels (ORCID: https://orcid.org/0000-0002-6857-5922)
- Roser Vento‐Tormo (ORCID: https://orcid.org/0000-0002-9870-8474)
- Geoffrey Schiebinger (ORCID: https://orcid.org/0000-0002-8290-7997)
- Jing-Qi Zhang (ORCID: https://orcid.org/0000-0002-1434-9014)
- Peter W. Zandstra (ORCID: https://orcid.org/0000-0002-9568-733X)
- John M. Edgar (ORCID: https://orcid.org/0000-0001-5678-6485)
- Tiam Heydari (ORCID: https://orcid.org/0000-0003-0465-8312)
- Yvonne Chung
- Becca Bonham-Carter (ORCID: https://orcid.org/0000-0003-0163-4673)
- Roser Vilarrasa‐Blasi (ORCID: https://orcid.org/0000-0002-3384-0693)
- Seungjoon Kim (ORCID: https://orcid.org/0000-0001-6298-5552)
- David J. H. F. Knapp (ORCID: https://orcid.org/0000-0002-2161-9959)
- Matthew C. Major
- Tara Stach (ORCID: https://orcid.org/0000-0002-5611-6139)
- M. Iliana Ibañez-Rios (ORCID: https://orcid.org/0000-0002-9153-2963)
- Laura Greenstreet (ORCID: https://orcid.org/0000-0003-0635-3870)
- Carla Zimmerman (ORCID: https://orcid.org/0000-0002-5132-2101)
- Nico Werschler
- Elizabeth L. Castle
- M. Siu (ORCID: https://orcid.org/0000-0002-5485-8606)
Institutions
- University of British Columbia (CA)
- Wellcome Sanger Institute (GB)
- CancerCare Manitoba (CA)
- Institute for Research in Immunology and Cancer (CA)
- Canada's Michael Smith Genome Sciences Centre (CA)
- Research Institute in Oncology and Hematology (CA)
- University of Manitoba (CA)
- University of Maine (US)
Publication Details
- Journal
- Cell Systems
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1016/j.cels.2024.11.001
- Citations
- 10
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- European Molecular Biology Organization
- Allen Institute
- Michael Smith Health Research BC
- Royal Commission for the Exhibition of 1851