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

doi:10.1038/s41590-022-01167-5

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

Institute of Biomedical Research at the Faculty of Dental Medicine

Research output: Contribution to journal › Article › peer-review

9 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 language	American English
Pages (from-to)	505-517
Number of pages	13
Journal	Nature Immunology
Volume	23
Issue number	4
DOIs	https://doi.org/10.1038/s41590-022-01167-5
State	Published - Apr 2022

Bibliographical note

Funding Information:
We dedicate this work to the memory of T. Rolink, who has been a great mentor and a friend to all of us. His vision and passion for research will remain. We acknowledge C. Engdahl, G. Capoferri, M. Burgunder and S. Sikanjic for their contributions. We thank A. Offinger and L. Davidson and both teams of animal caretakers at the DBM Basel and NIDCR USA for constant support. Further we would like to acknowledge the Genomics Facility Basel (D-BSSE ETH Zürich) for generating the CITE-seq dataset. Calculations were performed at sciCORE ( http://scicore.unibas.ch/ ) scientific computing center at the University of Basel. We also thank Y. Belkaid, G. Trinchieri, A. Bhandoola and C. Dunbar for their inputs and discussion. This work was in part supported by the SNF grants PP00P3_179056, 310030_185193 and by the Research Fund of the University of Basel for the promotion of excellent junior researchers (FK). This research was in part supported by the Intramural Research Program of the NIH, NIDCR (ZIADE000752-02).

Funding Information:
We dedicate this work to the memory of T. Rolink, who has been a great mentor and a friend to all of us. His vision and passion for research will remain. We acknowledge C. Engdahl, G. Capoferri, M. Burgunder and S. Sikanjic for their contributions. We thank A. Offinger and L. Davidson and both teams of animal caretakers at the DBM Basel and NIDCR USA for constant support. Further we would like to acknowledge the Genomics Facility Basel (D-BSSE ETH Zürich) for generating the CITE-seq dataset. Calculations were performed at sciCORE (http://scicore.unibas.ch/) scientific computing center at the University of Basel. We also thank Y. Belkaid, G. Trinchieri, A. Bhandoola and C. Dunbar for their inputs and discussion. This work was in part supported by the SNF grants PP00P3_179056, 310030_185193 and by the Research Fund of the University of Basel for the promotion of excellent junior researchers (FK). This research was in part supported by the Intramural Research Program of the NIH, NIDCR (ZIADE000752-02).

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

Keywords

Animals
Cell Differentiation
Cell Lineage/genetics
DNA Nucleotidylexotransferase/genetics
Hematopoietic Stem Cells/physiology
Mice
Mice, Transgenic
Multipotent Stem Cells

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10.1038/s41590-022-01167-5

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title = "Dntt expression reveals developmental hierarchy and lineage specification of hematopoietic progenitors",

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.",

keywords = "Animals, Cell Differentiation, Cell Lineage/genetics, DNA Nucleotidylexotransferase/genetics, Hematopoietic Stem Cells/physiology, Mice, Mice, Transgenic, Multipotent Stem Cells",

author = "Fabian Klein and Julien Roux and Grozdan Cvijetic and Rodrigues, {Patrick Fernandes} and {von Muenchow}, Lilly and Ruth Lubin and Pawel Pelczar and Simon Yona and Panagiotis Tsapogas and Roxane Tussiwand",

note = "Funding Information: We dedicate this work to the memory of T. Rolink, who has been a great mentor and a friend to all of us. His vision and passion for research will remain. We acknowledge C. Engdahl, G. Capoferri, M. Burgunder and S. Sikanjic for their contributions. We thank A. Offinger and L. Davidson and both teams of animal caretakers at the DBM Basel and NIDCR USA for constant support. Further we would like to acknowledge the Genomics Facility Basel (D-BSSE ETH Z{\"u}rich) for generating the CITE-seq dataset. Calculations were performed at sciCORE ( http://scicore.unibas.ch/ ) scientific computing center at the University of Basel. We also thank Y. Belkaid, G. Trinchieri, A. Bhandoola and C. Dunbar for their inputs and discussion. This work was in part supported by the SNF grants PP00P3_179056, 310030_185193 and by the Research Fund of the University of Basel for the promotion of excellent junior researchers (FK). This research was in part supported by the Intramural Research Program of the NIH, NIDCR (ZIADE000752-02). Funding Information: We dedicate this work to the memory of T. Rolink, who has been a great mentor and a friend to all of us. His vision and passion for research will remain. We acknowledge C. Engdahl, G. Capoferri, M. Burgunder and S. Sikanjic for their contributions. We thank A. Offinger and L. Davidson and both teams of animal caretakers at the DBM Basel and NIDCR USA for constant support. Further we would like to acknowledge the Genomics Facility Basel (D-BSSE ETH Z{\"u}rich) for generating the CITE-seq dataset. Calculations were performed at sciCORE (http://scicore.unibas.ch/) scientific computing center at the University of Basel. We also thank Y. Belkaid, G. Trinchieri, A. Bhandoola and C. Dunbar for their inputs and discussion. This work was in part supported by the SNF grants PP00P3_179056, 310030_185193 and by the Research Fund of the University of Basel for the promotion of excellent junior researchers (FK). This research was in part supported by the Intramural Research Program of the NIH, NIDCR (ZIADE000752-02). Publisher Copyright: {\textcopyright} 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2022",

month = apr,

doi = "10.1038/s41590-022-01167-5",

language = "American English",

volume = "23",

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journal = "Nature Immunology",

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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

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PY - 2022/4

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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.

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KW - Cell Differentiation

KW - Cell Lineage/genetics

KW - DNA Nucleotidylexotransferase/genetics

KW - Hematopoietic Stem Cells/physiology

KW - Mice

KW - Mice, Transgenic

KW - Multipotent Stem Cells

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JF - Nature Immunology

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ER -

Dntt expression reveals developmental hierarchy and lineage specification of hematopoietic progenitors

Abstract

Bibliographical note

Keywords

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