EBF1-deficient bone marrow stroma elicits persistent changes in HSC potential

Derecka, Marta; Herman, Josip Stefan; Cauchy, Pierre; Ramamoorthy, Senthilkumar; Lupar, Ekaterina; Grün, Dominic; Grosschedl, Rudolf

doi:10.1038/s41590-020-0595-7

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EBF1-deficient bone marrow stroma elicits persistent changes in HSC potential

MPS-Authors

Derecka, Marta
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Herman, Josip Stefan
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Cauchy, Pierre
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Ramamoorthy, Senthilkumar
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lupar, Ekaterina
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Grün, Dominic
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Grosschedl, Rudolf
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://www.nature.com/articles/s41590-020-0595-7
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Citation

Derecka, M., Herman, J. S., Cauchy, P., Ramamoorthy, S., Lupar, E., Grün, D., et al. (2020). EBF1-deficient bone marrow stroma elicits persistent changes in HSC potential. Nature, 21, 261-273. doi:10.1038/s41590-020-0595-7.

Cite as: https://hdl.handle.net/21.11116/0000-0005-BD60-A

Abstract

Crosstalk between mesenchymal stromal cells (MSCs) and hematopoietic stem cells (HSCs) is essential for hematopoietic homeostasis and lineage output. Here, we investigate how transcriptional changes in bone marrow (BM) MSCs result in long-lasting effects on HSCs. Single-cell analysis of Cxcl12-abundant reticular (CAR) cells and PDGFRα+Sca1+ (PαS) cells revealed an extensive cellular heterogeneity but uniform expression of the transcription factor gene Ebf1. Conditional deletion of Ebf1 in these MSCs altered their cellular composition, chromatin structure and gene expression profiles, including the reduced expression of adhesion-related genes. Functionally, the stromal-specific Ebf1 inactivation results in impaired adhesion of HSCs, leading to reduced quiescence and diminished myeloid output. Most notably, HSCs residing in the Ebf1-deficient niche underwent changes in their cellular composition and chromatin structure that persist in serial transplantations. Thus, genetic alterations in the BM niche lead to long-term functional changes of HSCs.