Single-cell characterization of haematopoietic progenitors and their trajectories in homeostasis and perturbed haematopoiesis

Amir Giladi; Franziska Paul; Yoni Herzog; Yaniv Lubling; Assaf Weiner; Ido Yofe; Diego Jaitin; Nina Cabezas-Wallscheid; Regine Dress; Florent Ginhoux; Andreas Trumpp; Amos Tanay; Ido Amit

doi:10.1038/s41556-018-0121-4

Single-cell characterization of haematopoietic progenitors and their trajectories in homeostasis and perturbed haematopoiesis

Nat Cell Biol. 2018 Jul;20(7):836-846. doi: 10.1038/s41556-018-0121-4. Epub 2018 Jun 18.

Authors

Amir Giladi¹, Franziska Paul¹, Yoni Herzog², Yaniv Lubling², Assaf Weiner¹, Ido Yofe¹, Diego Jaitin¹, Nina Cabezas-Wallscheid^{3

4

5}, Regine Dress⁶, Florent Ginhoux⁶, Andreas Trumpp³, Amos Tanay⁷, Ido Amit⁸

Affiliations

¹ Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
² Department of Computer Science and Applied Mathematics, Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
³ Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
⁴ Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.
⁵ Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
⁶ Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
⁷ Department of Computer Science and Applied Mathematics, Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. [email protected].
⁸ Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. [email protected].

PMID: 29915358
DOI: 10.1038/s41556-018-0121-4

Abstract

The dynamics of haematopoietic stem cell differentiation and the hierarchy of oligopotent stem cells in the bone marrow remain controversial. Here we dissect haematopoietic progenitor populations at single cell resolution, deriving an unbiased reference model of transcriptional states in normal and perturbed murine bone marrow. We define the signature of the naive haematopoietic stem cell and find a continuum of core progenitor states. Core cell populations mix transcription of pre-myeloid and pre-lymphoid programs, but do not mix erythroid or megakaryocyte programs with other fates. CRISP-seq perturbation analysis confirms our models and reveals that Cebpa regulates entry into all myeloid fates, while Irf8 and PU.1 deficiency block later differentiation towards monocyte or granulocyte fates. Our transcriptional map defines a reference network model for blood progenitors and their differentiation trajectories during normal and perturbed haematopoiesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CCAAT-Enhancer-Binding Proteins / genetics
CCAAT-Enhancer-Binding Proteins / metabolism
CRISPR-Cas Systems
Cell Lineage / genetics
Cell Proliferation / genetics
Cells, Cultured
Cellular Senescence / genetics
Erythropoietin / pharmacology
Female
Filgrastim / pharmacology
Gene Editing
Gene Expression Profiling / methods*
Gene Expression Regulation
Genotype
Hematinics / pharmacology
Hematopoiesis / drug effects
Hematopoiesis / genetics*
Hematopoietic Stem Cells / drug effects
Hematopoietic Stem Cells / metabolism
Hematopoietic Stem Cells / physiology*
Homeostasis
Interferon Regulatory Factors / genetics
Interferon Regulatory Factors / metabolism
Mice, Inbred C57BL
Phenotype
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Recombinant Proteins / pharmacology
Single-Cell Analysis / methods*
Time Factors
Trans-Activators / genetics
Trans-Activators / metabolism
Transcriptome*

Substances

CCAAT-Enhancer-Binding Proteins
CEBPA protein, mouse
Hematinics
Interferon Regulatory Factors
Proto-Oncogene Proteins
Recombinant Proteins
Trans-Activators
epoetin beta
interferon regulatory factor-8
proto-oncogene protein Spi-1
Erythropoietin
Filgrastim