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Single cell RNA seq of mouse bone marow-derived hematopoietic stem progenitor cells

ABSTRACT: Hematopoietic stem cells (HSCs) have been considered to progressively lose the self-renewal and differentiation potentials towards the commitment to each blood lineage. However, recent studies have suggested megakaryocyte progenitors are generated in a close relation with HSCs. In this study, we identified CD201-CD48- or CD48+ CD150+CD34-Kit+Sca-1+Lin- cells as new early megakaryocyte progenitors (MegP) in adult mouse bone marrow by single-cell (sc) transplantation, sc colony assay, sc RT-PCR, and sc RNA-sequencing. These MegP had little repopulating potential in vivo but formed megakaryocyte colonies in vitro. Transcriptome analysis suggested that these MegP lie downstream of HSCs and upstream of multipotent progenitors in a megakaryocyte differentiation pathway. The polyinosinic-polycytidylic acid (polyIC) injection and long-term reconstitution data suggested that a proportion of MegP expand after inflammation and transplantation. Here we propose a new model of HSC differentiation where HSCs give rise to common myeloid progenitors and MegP with little repopulating activity.

ORGANISM(S): Mus musculus

PROVIDER: GSE135013 | GEO | 2022/07/29

REPOSITORIES: GEO

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Project description:Haematopoietic stem cells (HSCs) are derived early from embryonic precursor cells, such as haemogenic endothelial cells and pre-HSCs. However, the identity of precursor cells remains elusive due to their rareness, transience, and inability to be isolated efficiently. Here we employed potent surface markers to capture the nascent pre-HSCs at 30% purity, as rigorously validated by single-cell-initiated serial transplantation assay. Then we applied single-cell RNA-Seq technique to analyse five populations closely related to HSC formation: endothelial cells, CD45- and CD45+ pre-HSCs in E11 aorta-gonad-mesonephros (AGM) region, and mature HSCs in E12 and E14 foetal liver. In comparison, the pre-HSCs showed unique features in transcriptional machinery, apoptosis, metabolism state, signalling pathway, transcription factor network, and lncRNA expression pattern. Among signalling pathways enriched in pre-HSCs, the mTOR activation was uncovered indispensable for the emergence of HSCs but not haematopoietic progenitors from endothelial cells in vivo. By comparing with proximal populations without HSC potential, the core molecular signature of pre-HSCs was identified. Collectively, our work paves the way for dissection of complex molecular mechanisms regulating the step-wise generation of HSCs in vivo, informing future efforts to engineer HSCs for clinical application. RNA-Seq of 181 single-cell samples from 8 FACS sorted cell types: 1. endothelial cells (samples E11.0_EC_xxxx. CD31+ VE-cadherin+CD41-CD43-CD45-Ter119-); 2. T1 pre-HSCs (samples E11.0_T1_xxxx. CD31+CD45-CD41low c-Kit+CD201high); 3. T1 CD201- cells (samples E11.0_T1CD201neg_xxxx, CD31+CD45-CD41low c-Kit+CD201low/-) ; 4. T2 pre-HSCs (samples E11.0_T2_35xx. CD31+CD45+c-Kit+CD201high), 5. T2 CD41low (samples E11.0_T2_21xx, E11.0_T2_24xx and E11.0_T2_27xx. CD31+CD45+CD41low); 6. E12 HSCs (samples E12.5_FL_xxxx. Lin-Sca-1+Mac-1lowCD201+); 7. E14 HSCs (samples E14.5_FL_xxxx. CD45+CD150+CD48-CD201+); 8. Adult HSCs (samples Adult_HSC_xxxx. CD45+CD150+CD48-CD201+). ECs, T1 pre-HSCs, T1 CD201- cells, T2 pre-HSCs, T2 CD41low cells were sorted from E11 AGM region. Mature HSCs were sorted from E12 or E14 fetal liver and adult bonemarrow.

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Single cell RNA seq of mouse bone marow-derived hematopoietic stem progenitor cells

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