Niche signals regulate continuous transcriptional states in hematopoietic stem cells

Abstract

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 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. Niche perturbations induce novel and rapid transitions between these HSC states. Differential expression analysis within each state revealed HSC- and LSK-specific molecular signatures for each perturbation. Chromatin analysis of unperturbed HSCs and LSKs by scATAC-Seq revealed HSC-specific, cell intrinsic predispositions to niche signals. We compiled a comprehensive resource of HSC- and progenitor-specific chromatin and transcriptional features that represent important determinants of regenerative potential during stress hematopoiesis.

Stimulation-responsive enhancers regulate inflammatory gene activation through retention and modification of H2A.Z-variant accessible nucleosomes

“…During normal homeostasis and in conditions of stress such as injury or inflammation, HSPCs maintain an appropriate balance of the hematopoietic system. HSPCs sense and respond to a variety of extrinsic signals that regulate their quiescence, proliferation, and differentiation 3,4 . A main mechanism of adaptation involves the activation of TFs that are downstream of signal transduction pathways to ensure appropriate transcriptional responses upon stimulation 5,6 .…”