Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
Audrey Sporrij
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
Margot Manning
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
Edroaldo Lummertz Rocha
Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
Song Yang
Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States
Yi Zhou
Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States
Jimin Guo
Medical Devices Research Centre, National Research Council Canada, Boucherville, Canada
Ninib Baryawno
Childhood Cancer Research Unit, Department of Children's and Women's Health, Karolinska Institutet, Stockholm, Sweden
Nikolaos Barkas
Broad Institute of Harvard and MIT, Cambridge, United States
David Scadden
Harvard University, Cambridge, United States
Fernando Camargo
Children's Hospital Harvard Med Sch, Cambridge, United States
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.
