External 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 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.

MicroRNA-221/222-expression in HSC and MPP safeguards their quiescence and multipotency by downregulating stress-independent and dependent expression of IEG and of several myelo/granulopoiesis-enhancing target genes

“…Our findings, that miR-221/222-deficiency-induced up-regulation of the Fos/AP-1/IEGs, appears sufficient to activate HSC, gives the Fos/AP-1-transcription factors a dominant controlling influence on transcription of only a limited number of IEG, activating HSC from quiescence to cell cycle and to increased granulopoiesis. We show here, that social as well as "in vitro" stress uses these pathways to Since AP-1 can be expected to regulate the expression of many more genes expressed in HSC, it remains to be investigated, how miR-221/222-deficiency focuses its effect in HSC to this selective set of genes, thereby conditioning them for myeloid-granulocytic development (76).…”

“…We show here, that social as well as "in vitro" stress uses these pathways to activate miR-221/222-proficient HSC. Our findings, that Fos/AP-1 upregulation in miR- Since AP-1 can be expected to regulate the expression of many more genes expressed in HSC, it remains to be investigated, how miR-221/222-deficiency focuses its effect in HSC to this selective set of genes, thereby conditioning them for myeloid-granulocytic development (76).…”

A Shape Sensing Mechanism driven by Arp2/3 and cPLA2licenses Dendritic Cells for Migration to Lymph Nodes in Homeostasis

“…Activation of cPLA 2 has been associated to transcriptional changes in different cell types (52; 53; 54; 55). We thus asked whether induction of CCR7 expression was part of a global transcriptional program triggered upon nucleus deformation.…”

Type 1 interferon remodels normal and neoplastic hematopoiesis in human

“…Consistent with this inference, we identified a downregulation of CXCR4 linked with their changes in proliferation status upon IFNa treatment. Moreover, as scRNA-seq of HSPCs from mice treated with the IFNa-inducing polyI:C 77 or infected with Mycobacterium tuberculosis 82 (a model of IFNa signaling) did not reveal a comparable population, there is a possibility that the corresponding IGP population may not be present in mice.…”