Single Cell Phenotyping Reveals Heterogeneity Among Hematopoietic Stem Cells Following Infection

MacLean, Adam L.; Smith, Maia A.; Liepe, Juliane; Sim, Aaron; Khorshed, Reema; Rashidi, Narges; Scherf, Nico; Krinner, Axel; Roeder, Ingo; Celso, Cristina Lo; Stumpf, Michael

doi:10.1002/stem.2692

Cited by 17 publications

(18 citation statements)

References 69 publications

(92 reference statements)

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“…The CD317 expression pattern is providing the first direct evidence that all HSCs rapidly react to IFN, suggesting that the bone marrow niche is highly permeable in the context of immune stimulation. The observed heterogeneity in CD69 expression is in agreement with a functional heterogeneity among HSCs following infection [ 6 ], and suggests future functional assessment of HSC’s sub-populations. Interestingly, a very-recent study demonstrated potential mobilization and activation of HSCs and progenitors in a human-CD69 mouse model [ 15 ], suggesting further interest in this receptor.…”

supporting

confidence: 59%

Identification of immune-activated hematopoietic stem cells

et al. 2018

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supporting

confidence: 59%

Identification of immune-activated hematopoietic stem cells

et al. 2018

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“…These aged HSCs may arise from either the cell-intrinsic transition of balanced to myeloid-biased LT-HSCs or the clonal expansion of preexisting fractions of myeloid-biased LT-HSCs (13,14,16,20,21). Several studies support the presence of preexisting myeloid-biased LT-HSCs by demonstrating that myeloid-biased subpopulations of LT-HSCs in young, healthy mice respond to environmental challenges, such as inflammation and infection (22,23). Results from lineage tracing with genetic barcodes (24,25) and single cell transplants of LT-HSCs also support the notion of inherent functional diversity among LT-HSCs (26)(27)(28).…”

mentioning

confidence: 99%

Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5 ⁺ mouse long-term hematopoietic stem cells

Gulati

Żukowska

Noh

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Hematopoietic stem cells (HSCs) self-renew and generate all blood cells. Recent studies with single cell transplants and lineage tracing suggest that adult HSCs are diverse in their reconstitution and lineage potentials. However, prospective isolation of these subpopulations has remained challenging. Here, we identify Neogenin-1 (NEO1) as a unique surface marker on a fraction of mouse HSCs labeled with Hoxb5, a specific reporter of long-term HSCs (LT-HSCs). We show that NEO1+Hoxb5+ LT-HSCs expand with age and respond to myeloablative stress in young mice while NEO1−Hoxb5+ LT-HSCs exhibit no significant change in number. Furthermore, NEO1+Hoxb5+ LT-HSCs are more often in the G2/S cell cycle phase compared to NEO1−Hoxb5+ LT-HSCs in both young and old bone marrow. Upon serial transplantation, NEO1+Hoxb5+ LT-HSCs exhibit myeloid-biased differentiation and reduced reconstitution while NEO1−Hoxb5+ LT-HSCs are lineage-balanced and stably reconstitute recipients. Gene expression analysis reveals erythroid and myeloid priming in the NEO1+ fraction and association of quiescence and self-renewal–related transcription factors with NEO1− LT-HSCs. Finally, transplanted NEO1+Hoxb5+ LT-HSCs rarely generate NEO1−Hoxb5+ LT-HSCs while NEO1−Hoxb5+ LT-HSCs repopulate both LT-HSC fractions. This supports a model in which dormant, balanced NEO1−Hoxb5+ LT-HSCs can hierarchically precede active, myeloid-biased NEO1+Hoxb5+ LT-HSCs.

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“…Previous studies have shown that a subpopulation of pHSCs expands with age 15,23 and responds to environmental challenge 18,19 . However, the effect of aging and stress on LT-HSCs and their subpopulations have not yet been evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…Although Hoxb5 + LT-HSCs are long-term self-renewing cells, it is unknown whether they contain fractions with distinct functional properties. Increasing evidence suggests that subpopulations of LT-HSCs selectively respond to environmental stress conditions 18,19 and exhibit biases in lineage contribution 18 . Moreover, the selective and clonal expansion of a subset of LT-HSCs has been proposed to mediate the changes observed in hematopoiesis during aging 15,54 .…”

Section: Discussionmentioning

confidence: 99%

“…These aged HSCs may arise from either the cell-intrinsic transition of balanced to myeloid-biased LT-HSCs or the clonal expansion of pre-existing fractions of myeloid-biased LT-HSCs 10,11,15-17 . Several studies support the presence of pre-existing myeloid-biased LT-HSCs by demonstrating that myeloid-biased subpopulations of LT-HSCs in young, healthy mice respond to environmental challenges, such as inflammation and infection 18,19 . Results from lineage tracing with genetic barcodes 20,21 and single cell transplants of LT-HSCs also support the notion of inherent functional diversity among long-term repopulating HSCs 22-24 .…”

Section: Introductionmentioning

confidence: 99%

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Neogenin-1 distinguishes between myeloid-biased and balancedHoxb5⁺mouse long-term hematopoietic stem cells

Gulati

Żukowska

Noh

et al. 2019

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27Hematopoietic stem cells (HSCs) self-renew and generate all blood cells. Recent studies with 28 single-cell transplants and lineage tracing suggest that adult HSCs are diverse in their 29 reconstitution and lineage potentials. However, prospective isolation of these subpopulations 30 has remained challenging. Here, we identify Neogenin-1 (NEO1) as a novel surface marker on a 31 fraction of mouse HSCs labeled with Hoxb5, a specific reporter of long-term HSCs (LT-HSCs). 32We show that NEO1 + Hoxb5 + LT-HSCs are more proliferative and expand with age, while NEO1 -33 Hoxb5 + LT-HSCs remain largely quiescent with no significant increase in number. Upon serial 34 transplantation, NEO1 + Hoxb5 + LT-HSCs exhibit myeloid-biased differentiation and reduced 35 reconstitution, while NEO1 -Hoxb5 + LT-HSCs are lineage-balanced and stably reconstitute 36 recipients. Gene expression comparison further reveals evidence of lineage-priming in the 37 NEO1 + fraction. Finally, transplanted NEO1 + Hoxb5 + LT-HSCs rarely generate NEO1 -Hoxb5 + LT- 38HSCs, while NEO1 -Hoxb5 + LT-HSCs repopulate both LT-HSC fractions, supporting that NEO1 - 39Hoxb5 + LT-HSCs can hierarchically precede NEO1 + Hoxb5 + LT-HSCs. neuronal survival 30 , skeletal myofiber differentiation 31 , intracellular iron homeostasis 32 , mammary 80 epithelial development 33 , and endothelial migration 34 , as of yet, little is known about its role in 81 bone marrow hematopoiesis. We find that NEO1 + Hoxb5 + LT-HSCs represent a myeloid-biased 82 subset of LT-HSCs that responds to myeloablative stress and expands with age. Contrastingly, 83 NEO1 -Hoxb5 + LT-HSCs exhibit greater reconstitution potential, balanced lineage output, and a 84 more quiescent cell cycle status compared to NEO1 + Hoxb5 + LT-HSCs. After transplant, NEO1 - 85Hoxb5 + LT-HSCs give rise to NEO1 + Hoxb5 + LT-HSCs, but the reverse transition is rarely 86 observed. We, therefore, propose a model of early long-term hematopoiesis in which balanced, 87 quiescent LT-HSCs self-renew and generate long-term myeloid-biased LT-HSCs in response to 88 stress and during the course of aging. 89 RESULTS 91 Neogenin-1 (NEO1) marks a subpopulation of mouse Hoxb5 + LT-HSCs and human HSCs 92Functional heterogeneity within Hoxb5 + LT-HSCs is poorly understood. To identify surface 93 candidates that fractionate Hoxb5 + LT-HSCs, we first pattern-searched 64 microarray 94 expression profiles of 23 distinct mouse hematopoietic cell types 35 for (1) genes annotated to 95 code for cell surface proteins (GO Biological Process: 0009986) and (2) genes specifically 96 expressed in HSCs compared to downstream cell types ( Fig. 1a). We found several known 97 HSC-specific markers, including Robo4 36 , Slamf1 5 , Ly6a 2 , Vwf 26 , TEK 37 , and a member of the 98 Gpcr5 family 38 , validating the utility of our approach. We also identified several novel markers of 99 HSCs that have not been previously reported (Fig. 1a). Among the top 3 most enriched surface 100 markers on HSCs, Neogenin-1 (Neo1) was more highly expressed on HSCs compared...

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Single Cell Phenotyping Reveals Heterogeneity Among Hematopoietic Stem Cells Following Infection

Cited by 17 publications

References 69 publications

Identification of immune-activated hematopoietic stem cells

Identification of immune-activated hematopoietic stem cells

Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5 ⁺ mouse long-term hematopoietic stem cells

Neogenin-1 distinguishes between myeloid-biased and balancedHoxb5⁺mouse long-term hematopoietic stem cells

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Single Cell Phenotyping Reveals Heterogeneity Among Hematopoietic Stem Cells Following Infection

Cited by 17 publications

References 69 publications

Identification of immune-activated hematopoietic stem cells

Identification of immune-activated hematopoietic stem cells

Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5 + mouse long-term hematopoietic stem cells

Neogenin-1 distinguishes between myeloid-biased and balancedHoxb5+mouse long-term hematopoietic stem cells

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Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5 ⁺ mouse long-term hematopoietic stem cells

Neogenin-1 distinguishes between myeloid-biased and balancedHoxb5⁺mouse long-term hematopoietic stem cells