Single-Cell Analysis of Neonatal HSC Ontogeny Reveals Gradual and Uncoordinated Transcriptional Reprogramming that Begins before Birth

Li, Yanan; Kong, Wenjun; Yang, Wei; Patel, Riddhi; Casey, Emily; Okeyo-Owuor, Theresa; White, Janicé; Porter, Shaina N.; Morris, Samantha A.; Magee, Jeffrey A.

doi:10.1016/j.stem.2020.08.001

Cited by 54 publications

(91 citation statements)

References 93 publications

(103 reference statements)

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“…Moreover, by ranking differential gene expression of CB and aBM based on their occurrence in clusters, a continuous acquisition of an aged gene expression profile from CB, through yBM to aBM was observed. This gradual development of ageing mirrors recent findings within the mouse system, where scRNA-seq and epigenetic analysis have shown that the foetal to adult transition is a continuous process[44]. Thus, HSPCs are constantly ageing, resulting in global effects on gene expression and cell population heterogeneities.…”

Section: Discussionsupporting

confidence: 75%

Single-Cell Multiomics Reveals Distinct Cell States at the Top of the Human Hematopoietic Hierarchy

Sommarin

Dhapola

Safi

et al. 2021

Preprint

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The advent of single cell (Sc) genomics has challenged the dogma of haematopoiesis as a tree-like structure of stepwise lineage commitment through distinct and increasingly restricted progenitor populations. Instead, analysis of ScRNA-seq has proposed that the earliest events in human hematopoietic stem cell (HSC) differentiation are characterized by only subtle molecular changes, with hematopoietic stem and progenitor cells (HSPCs) existing as a continuum of low-primed cell-states that gradually transition into a specific lineage (CLOUD-HSPCs). Here, we combine ScRNA-seq, ScATAC-seq and cell surface proteomics to dissect the heterogeneity of CLOUD-HSPCs at different stages of human life. Within CLOUD-HSPCs, pseudotime ordering of both mRNA and chromatin data revealed a bifurcation of megakaryocyte/erythroid and lympho/myeloid trajectories immediately downstream a subpopulation with an HSC-specific enhancer signature. Importantly, both HSCs and lineage-restricted progenitor populations could be prospectively isolated based on correlation of their molecular signatures with CD35 and CD11A expression, respectively. Moreover, we describe the changes that occur in this heterogeneity as hematopoiesis develops from neonatal to aged bone marrow, including an increase of HSCs and depletion of lympho-myeloid biased MPPs. Thus, this study dissects the heterogeneity of human CLOUD-HSPCs revealing distinct HSPC-states of relevance in homeostatic settings such as ageing.

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Section: Discussionsupporting

confidence: 75%

Single-Cell Multiomics Reveals Distinct Cell States at the Top of the Human Hematopoietic Hierarchy

Sommarin

Dhapola

Safi

et al. 2021

Preprint

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“…Although it is unclear which factors activate autophagy, it is assumed that autophagy is important for survival of HSCs against specific harsh neonatal environments. To understand the neonatal period better, we analyzed public RNA-seq data from wild type neonatal (P7) HSCs (CD48 -CD150 + Lineage -Sca-1 + c-Kit -) and adult HSCs deposited in GEO (GSE128762) 40 . We found that expression of many genes involved in glucose and glutamine metabolisms, mitochondria, and redox regulation varied significantly between at P7 and adult mice.…”

Section: Discussionmentioning

confidence: 99%

Essential role of autophagy in protecting neonatal haematopoietic stem cells from oxidative stress in a p62-independent manner

Nomura

Ito

Ooshio

et al. 2021

Sci Rep

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Autophagy is a cellular degradation system contributing to homeostasis of tissue stem cells including haematopoietic stem cells (HSCs). It plays pleiotropic roles in HSC characteristics throughout life, but its stage-specific roles in HSC self-renewal are unclear. To investigate the effects of Atg5 deletion on stage-specific HSC functions, we compared the repopulating capacity of HSCs in Atg5f/f;Vavi-cre mice from postnatal day (P) 0–7 weeks of age. Interestingly, Atg5 deficiency led to no remarkable abnormality in the HSC self-renewal capacity at P0, but significant defects at P7, followed by severe defects. Induction of Atg5 deletion at P5 by tamoxifen administration to Atg5f/f;Rosa26-Cre-ERT2 mice resulted in normal haematopoiesis, including the HSC population, until around 1 year, suggesting that Atg5 in the early neonatal period was critical for haematopoiesis in adults. Mitochondrial oxidative stress was increased by Atg5 loss in neonatal HSC/progenitor cells. Although p62 had accumulated in immature bone marrow cells of Atg5f/f;Vavi-cre mice, p62 deletion did not restore defective HSC functions, indicating that Atg5-dependent haematopoietic regulation in the developmental period was independent of p62. This study proposes a critical role of autophagy in HSC protection against harsh environments in the early neonatal stage, which is essential for healthy long-term haematopoiesis.

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“…Fetal HSCs are more self-renewing and proliferating than the adult counterpart, not adapting an adult-like state until around 3 weeks after birth ( Bowie et al, 2006 ). How this transition from fetal to adult is regulated was recently investigated in mouse development, where scRNA-seq was combined with bulk ATAC-seq and ChIP-seq to investigate the transcriptional and epigenomic landscapes at different timepoints from E16 to adult ( Li et al, 2020 ). The postnatal samples clustered separately from fetal and adult samples, indicating a gradual switch toward adult state.…”

Section: Describing Fetal To Adult Transition With Single-cell Methodsmentioning

confidence: 99%

Defining the Emerging Blood System During Development at Single-Cell Resolution

Karlsson

Sommarin

Böiers

2021

Front. Cell Dev. Biol.

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Developmental hematopoiesis differs from adult and is far less described. In the developing embryo, waves of lineage-restricted blood precede the ultimate emergence of definitive hematopoietic stem cells (dHSCs) capable of maintaining hematopoiesis throughout life. During the last two decades, the advent of single-cell genomics has provided tools to circumvent previously impeding characteristics of embryonic hematopoiesis, such as cell heterogeneity and rare cell states, allowing for definition of lineage trajectories, cellular hierarchies, and cell-type specification. The field has rapidly advanced from microfluidic platforms and targeted gene expression analysis, to high throughput unbiased single-cell transcriptomic profiling, single-cell chromatin analysis, and cell tracing—offering a plethora of tools to resolve important questions within hematopoietic development. Here, we describe how these technologies have been implemented to address a wide range of aspects of embryonic hematopoiesis ranging from the gene regulatory network of dHSC formation via endothelial to hematopoietic transition (EHT) and how EHT can be recapitulated in vitro, to hematopoietic trajectories and cell fate decisions. Together, these studies have important relevance for regenerative medicine and for our understanding of genetic blood disorders and childhood leukemias.

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Single-Cell Analysis of Neonatal HSC Ontogeny Reveals Gradual and Uncoordinated Transcriptional Reprogramming that Begins before Birth

Cited by 54 publications

References 93 publications

Single-Cell Multiomics Reveals Distinct Cell States at the Top of the Human Hematopoietic Hierarchy

Single-Cell Multiomics Reveals Distinct Cell States at the Top of the Human Hematopoietic Hierarchy

Essential role of autophagy in protecting neonatal haematopoietic stem cells from oxidative stress in a p62-independent manner

Defining the Emerging Blood System During Development at Single-Cell Resolution

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