TY - JOUR
T1 - Dntt expression reveals developmental hierarchy and lineage specification of hematopoietic progenitors
AU - Klein, Fabian
AU - Roux, Julien
AU - Cvijetic, Grozdan
AU - Rodrigues, Patrick Fernandes
AU - von Muenchow, Lilly
AU - Lubin, Ruth
AU - Pelczar, Pawel
AU - Yona, Simon
AU - Tsapogas, Panagiotis
AU - Tussiwand, Roxane
N1 - Publisher Copyright:
© 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85127393514&partnerID=8YFLogxK
U2 - 10.1038/s41590-022-01167-5
DO - 10.1038/s41590-022-01167-5
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C2 - 35354960
AN - SCOPUS:85127393514
SN - 1529-2908
VL - 23
SP - 505
EP - 517
JO - Nature Immunology
JF - Nature Immunology
IS - 4
ER -