External signals regulate continuous transcriptional states in hematopoietic stem cells

• Published in: eLife Vol. 10
• Main Authors: Fast, Eva M, Sporrij, Audrey, Manning, Margot, Rocha, Edroaldo Lummertz, Yang, Song, Zhou, Yi, Guo, Jimin, Baryawno, Ninib, Barkas, Nikolaos, Scadden, David, Camargo, Fernando, Zon, Leonard I
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 23.12.2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Analysis; Animals; Approximation; Ataxin; Biological response modifiers; blood; c-Kit protein; Cell Lineage; Chromatin; Colony-stimulating factor; Epigenetics; External stimuli; Female; Gene expression; Gene Expression Regulation - physiology; Genetic aspects; Genetic transcription; Genomics; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - drug effects; growth factors; Hematopoietic stem cells; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Homeostasis; Interferon; interferons; Interferons - drug effects; Leukocytes (granulocytic); Male; Mice; Multipotent Stem Cells - drug effects; Multipotent Stem Cells - metabolism; Progenitor cells; prostaglandins; Prostaglandins - metabolism; RNA sequencing; Sequence Analysis, RNA; Signal Transduction; stem cell niche; Stem cell transplantation; Stem cells; Stem Cells and Regenerative Medicine; Stimulants; Transcription; Transcriptome; Transplantation; Transplants & implants; Canada; mouse; stem cells; stem cell niche; interferons; growth factors; regenerative medicine; prostaglandins; chromatin; blood
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.66512

Hematopoietic stem cells (HSCs) must ensure adequate blood cell production following distinct external stressors. A comprehensive understanding of in vivo heterogeneity and specificity of HSC responses to external stimuli is currently lacking. We performed single-cell RNA sequencing (scRNA-Seq) on functionally validated mouse HSCs and LSK (Lin-, c-Kit+, Sca1+) progenitors after in vivo pharmacological perturbation of niche signals interferon, granulocyte colony-stimulating factor (G-CSF), and prostaglandin. We identified six HSC states that are characterized by enrichment but not exclusive expression of marker genes. External signals induced rapid transitions between HSC states but transcriptional response varied both between external stimulants and within the HSC population for a given perturbation. In contrast to LSK progenitors, HSCs were characterized by a greater link between molecular signatures at baseline and in response to external stressors. Chromatin analysis of unperturbed HSCs and LSKs by scATAC-Seq suggested some HSC-specific, cell intrinsic predispositions to niche signals. We compiled a comprehensive resource of HSC- and LSK progenitor-specific chromatin and transcriptional features that represent determinants of signal receptiveness and regenerative potential during stress hematopoiesis.