Inflammation-Induced Emergency Megakaryopoiesis Driven by Hematopoietic Stem Cell-like Megakaryocyte Progenitors

Haas, Simon; Hansson, Jenny; Klimmeck, Daniel; Loeffler, Dirk; Velten, Lars; Uckelmann, Hannah J.; Wurzer, Stephan; Prendergast, Áine M.; Schnell, Alexandra; Hexel, Klaus; Santarella-Mellwig, Rachel; Blaszkiewicz, Sandra; Kuck, Andrea; Geiger, Hartmut; Milsom, Michael D.; Steinmetz, Lars M.; Schroeder, Timm; Trumpp, Andreas; Krijgsveld, Jeroen; Essers, Marieke

doi:10.1016/j.stem.2015.07.007

Cited by 373 publications

(421 citation statements)

References 41 publications

Supporting

Mentioning

393

Contrasting

Unclassified

Order By: Relevance

“…Combining our dual detection with other emerging technologies may allow further refinement in the MEP population. Alternate hierarchical models of hematopoiesis have been proposed, wherein a pool of long-term self-renewing stem cells or cells that have the surface phenotype of HSCs and MPPs are already Mk committed 39 or have the ability to commit directly to the Mk lineage. 40 In addition to murine studies cited in the introduction and above, a recently published study suggests that in adult humans, Mk/E activity together with multipotency are restricted to the stem cell compartment with no intermediate bipotent progenitor.…”

Section: Cd41mentioning

confidence: 99%

Adult human megakaryocyte-erythroid progenitors are in the CD34+CD38mid fraction

Sanada¹,

Xavier-Ferrucio

et al. 2016

Blood

View full text Add to dashboard Cite

• Purification strategies developed for human Mk-E progenitors, as well as committed Mk and E progenitors.• MYB regulates the biphenotypic fate decision of human MEPs.Bipotent megakaryocyte/erythroid progenitors (MEPs) give rise to progeny limited to the megakaryocyte (Mk) and erythroid (E) lineages. We developed a novel dual-detection functional in vitro colony-forming unit (CFU) assay for single cells that differentiates down both the Mk and E lineages (CFU-Mk/E), which allowed development and validation of a novel purification strategy for the identification and quantitation of primary functional human MEPs from granulocyte colony-stimulating factor-mobilized peripheral blood and bone marrow. Applying this assay to fluorescence-activated cell sorter-sorted cell populations, we found that the Lin2 population is much more highly enriched for bipotent MEPs than any previously reported subpopulations. We also developed purification strategies for primary human lineage-committed Mk and E progenitors identified as CFU-Mk and burst forming unit-E. Comparative expression analyses in MEP, MkP, and ErP populations revealed differential expression of MYB. We tested whether alterations in MYB concentration affect the Mk-E fate decision at the single cell level in MEPs and found that short hairpin RNA-mediated MYB knockdown promoted commitment of MEPs to the Mk lineage, further defining its role in MEP lineage fate. There are numerous applications for these novel enrichment strategies, including facilitating mechanistic studies of MEP lineage commitment, improving approaches for in vitro expansion of Mk and E cells, and developing improved therapies for benign and malignant hematologic disease. (Blood. 2016;128(7):923-933)

show abstract

Section: Cd41mentioning

confidence: 99%

Adult human megakaryocyte-erythroid progenitors are in the CD34+CD38mid fraction

Sanada¹,

Xavier-Ferrucio

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

“…CD41 has been reported to mark myeloid and megakaryocyte progenitors within the HSC compartment (Haas et al, 2015;Yamamoto et al, 2013), and it's expression increases with age (Gekas and Graf, 2013). Given that myeloid-restricted repopulating cells accumulate in aged mice (Dykstra et al, 2011;Sudo et al, 2000), we hypothesized that by examining CD41 expression we would better understand both the heterogeneity and the myeloid potential within aging HSC compartments.…”

Section: Increased Divisional History Marks Increased Myeloid Potentialmentioning

confidence: 96%

Hematopoietic stem cells count and remember self-renewal divisions

Bernitz¹,

MacArthur

Sieburg

et al. 2016

Experimental Hematology

View full text Add to dashboard Cite

SummaryThe ability of cells to count and remember their divisions could underlie many alterations that occur during development, aging, and disease. We tracked the cumulative divisional history of slow-cycling hematopoietic stem cells (HSCs) throughout adult life. This revealed a fraction of rarely dividing HSCs that contained all the long-term HSC (LT-HSC) activity within the aging HSC compartment. During adult life, this population asynchronously completes four traceable symmetric self-renewal divisions to expand its size before entering a state of dormancy. We show that the mechanism of expansion involves progressively lengthening periods between cell divisions, with long-term regenerative potential lost upon a fifth division. Our data also show that age-related phenotypic changes within the HSC compartment are divisional history dependent. These results suggest that HSCs accumulate discrete memory stages over their divisional history and provide evidence for the role of cellular memory in HSC aging. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Graphical AbstractHSCs count and remember the number of times they have divided to limit the number of cell divisions, a mechanism that may underlie HSC aging.

show abstract

“…However, a recent study 54 demonstrated the presence of a subset of megakaryocyte-committed cells within the immunophenotypically defined HSC compartment that becomes activated upon inflammatory stress to efficiently replenish platelets. During homeostasis, these so called stem-like megakaryocyte-committed progenitors (SL-MkPs) were shown to be mainly quiescent but primed to megakaryocyte commitment because transcripts that encoded several megakaryocyte-associated proteins were actively translated in response to inflammation, resulting in the generation of mature megakaryocytes.…”

Section: Cd42bmentioning

confidence: 99%

Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage

Woolthuis¹,

Park

2016

Blood

124

View full text Add to dashboard Cite

The classical model of hematopoiesis has long held that hematopoietic stem cells (HSCs) sit at the apex of a developmental hierarchy in which HSCs undergo long-term self-renewal while giving rise to cells of all the blood lineages. In this model, self-renewing HSCs progressively lose the capacity for self-renewal as they transit into short-term self-renewing and multipotent progenitor states, with the first major lineage commitment occurring in multipotent progenitors, thus giving rise to progenitors that initiate the myeloid and lymphoid branches of hematopoiesis. Subsequently, within the myeloid lineage, bipotent megakaryocyte-erythrocyte and granulocyte-macrophage progenitors give rise to unipotent progenitors that ultimately give rise to all mature progeny. However, over the past several years, this developmental scheme has been challenged, with the origin of megakaryocyte precursors being one of the most debated subjects. Recent studies have suggested that megakaryocytes can be generated from multiple pathways and that some differentiation pathways do not require transit through a requisite multipotent or bipotent megakaryocyte-erythrocyte progenitor stage. Indeed, some investigators have argued that HSCs contain a subset of cells with biased megakaryocyte potential, with megakaryocytes directly arising from HSCs under steady-state and stress conditions. In this review, we discuss the evidence supporting these nonclassical megakaryocytic differentiation pathways and consider their relative strengths and weaknesses as well as the technical limitations and potential pitfalls in interpreting these studies. Ultimately, such pitfalls will need to be overcome to provide a comprehensive and definitive understanding of megakaryopoiesis.

show abstract

Inflammation-Induced Emergency Megakaryopoiesis Driven by Hematopoietic Stem Cell-like Megakaryocyte Progenitors

Cited by 373 publications

References 41 publications

Adult human megakaryocyte-erythroid progenitors are in the CD34+CD38mid fraction

Adult human megakaryocyte-erythroid progenitors are in the CD34+CD38mid fraction

Hematopoietic stem cells count and remember self-renewal divisions

Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage

Contact Info

Product

Resources

About