Dntt expression reveals developmental hierarchy and lineage specification of hematopoietic progenitors

Fabian Klein, Julien Roux, Grozdan Cvijetic, Patrick Fernandes Rodrigues, Lilly von Muenchow, Ruth Lubin, Pawel Pelczar, Simon Yona, Panagiotis Tsapogas, Roxane Tussiwand*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Intrinsic and extrinsic cues determine developmental trajectories of hematopoietic stem cells (HSCs) towards erythroid, myeloid and lymphoid lineages. Using two newly generated transgenic mice that report and trace the expression of terminal deoxynucleotidyl transferase (TdT), transient induction of TdT was detected on a newly identified multipotent progenitor (MPP) subset that lacked self-renewal capacity but maintained multilineage differentiation potential. TdT induction on MPPs reflected a transcriptionally dynamic but uncommitted stage, characterized by low expression of lineage-associated genes. Single-cell CITE-seq indicated that multipotency in the TdT+ MPPs is associated with expression of the endothelial cell adhesion molecule ESAM. Stable and progressive upregulation of TdT defined the lymphoid developmental trajectory. Collectively, we here identify a new multipotent progenitor within the MPP4 compartment. Specification and commitment are defined by downregulation of ESAM which marks the progressive loss of alternative fates along all lineages.

Original languageAmerican English
Pages (from-to)505-517
Number of pages13
JournalNature Immunology
Volume23
Issue number4
DOIs
StatePublished - Apr 2022

Bibliographical note

Publisher Copyright:
© 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

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