Pf450 High Ploidy Large Cytoplasmic Megakaryocytes: Key Negative Regulators of Hematopoietic Stem Cells and Essential for Platelet Production

Heazlewood, Shen Y.; Ahmad, Tanveer; Cao, Benjamin; Cao, Huimin; Domingues, Mélanie J.; Williams, Brenda; Heazlewood, Celena; Fulton, Madeline; Li, S.; White, John; Kraus, Felix; Ryan, Michael J.; Kile, BT; Änkö, Minna‐Liisa; Nilsson, SK

doi:10.1097/01.hs9.0000560012.97655.67

Cited by 6 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, megakaryocytes were much larger in younger individuals compared to both older age groups (270.42±54.16 µm 2 vs. 178.06±58.56 µm 2 , p=0.0012), and, interestingly, megakaryocyte size showed a borderline-significant positive correlation with platelet counts (Spearman R =0.357, p=0.056) [Figure 3B, Supplemental Data Fig. 6]; a similar association has very recently been shown in mouse models, 62 and therefore we hypothesize that smaller megakaryocytes less efficiently produce proplatelets and/or platelet buds, leading to reduced platelet deposition into the peripheral circulation via sinusoids. Prior studies have identified an aging-associated bias toward megakaryopoiesis in preclinical models.…”

Section: Aging Is Associated With Morphologic Changes In Hspcs and Me...supporting

confidence: 76%

Single Cell Resolution Spatial Mapping of Human Hematopoiesis Reveals Aging-Associated Topographic Remodeling

Sarachakov

Svekolkin

Varlamova

et al. 2023

Preprint

View full text Add to dashboard Cite

The spatial anatomy of hematopoiesis in bone marrow has been extensively studied in mice and other preclinical models but technical challenges have precluded a commensurate exploration in humans. Institutional pathology archives contain many thousands of paraffinized bone marrow core biopsy tissue specimens, providing a rich resource for studying the intact human bone marrow topography in a variety of physiologic states. Thus, we developed an end-to-end pipeline involving multiparameter whole tissue staining, in situ imaging at single cell resolution, and AI-based digital image analysis, and then applied it to a cohort of disease-free samples to survey alterations in the hematopoietic topography associated with aging. Our data indicate heterogeneity in marrow adipose tissue (MAT) content within each age group, and an inverse correlation between MAT content and proportions of early myeloid and erythroid precursors, irrespective of age. We identify consistent endosteal and perivascular positioning of hematopoietic stem and progenitor cells (HSPCs) with medullary localization of more differentiated elements and, importantly, uncover new evidence of aging-associated changes in cellular and vascular morphologies, microarchitectural alterations suggestive of inflammaging, and diminution of a potentially active megakaryocytic niche. Our findings overall suggest that there is topographic remodeling of human hematopoiesis associated with aging. More generally, we demonstrate the potential to deeply unravel the spatial biology of normal and pathologic human bone marrow states using intact archival tissue specimens.

show abstract

Section: Aging Is Associated With Morphologic Changes In Hspcs and Me...supporting

confidence: 76%

Single Cell Resolution Spatial Mapping of Human Hematopoiesis Reveals Aging-Associated Topographic Remodeling

Sarachakov

Svekolkin

Varlamova

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Surprisingly, the canonical GFP+ MkPs maintain youthful properties throughout life, with relatively attenuated expansion and engraftment capacities that are indistinguishable from young GFP+ MkPs. The functional similarities of the young and aged GFP+ MkPs were unexpected, as we detected significant changes in gene expression ( Figure 3 ) and because the well-documented changes to the BM environment were expected to alter cell function (Frisch et al 2019; Stegner et al 2017; Heazlewood et al 2023; Zhao et al 2014; Bruns et al 2014; Ho et al 2019). Similar resilience to external factors has recently been reported for HSCs upon attempts to influence HSC aging by several heterochronic strategies (Ho et al 2021).…”

Section: Discussionmentioning

confidence: 79%

An age-specific platelet differentiation path from hematopoietic stem cells contributes to exacerbated thrombosis

Poscablo,

Worthington,

Smith-Berdan

et al. 2024

Preprint

View full text Add to dashboard Cite

SUMMARYPlatelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Hematopoietic stem and progenitor cells continuously give rise to platelets, but their contributions to variable platelet production and activity throughout life remain unclear. Here we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is unique to aging. An unequivocal genetic lineage tracing mouse model demonstrated that this age-specific pathway is progressively propagated over time. Remarkably, the age-specific platelet path is decoupled from all other hematopoietic lineages, including erythropoiesis, and operates as an additional layer in parallel with canonical platelet production. This results in two molecularly and functionally distinct populations of megakaryocyte progenitor cells that that operate in parallel. The age-specific megakaryocyte progenitor population has profoundly enhanced capacity to engraft, expand, and reconstitute platelets, and produces an additional platelet population that exists only in old mice. Consistent with increased thrombotic incidence upon aging, the two pools of co-existing platelets contribute to age-related thrombocytosis and dramatically increased thrombosisin vivo. Upon acute, platelet-specific stress, the age-specific MkPs endowed old mice with superior capacity to rapidly restore platelet counts. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and identify an aging-induced population of functionally enhanced MkPs as a unique source of age-specific platelets.>HIGHLIGHTSAging leads to two parallel platelet specification paths from HSCsThe shortcut platelet pathway is perpetuated by highly expansive MkPs unique to agingThe age-specific differentiation path contributes to thrombosis and platelet hyperreactivityAge-specific MkPs serve as potent first responders to acute platelet loss

show abstract

“…Here, high ploidy MKs that also contain a large cytoplasm were identified as the primary source of platelets. Through a mouse model involving the targeted deletion of the RNA binding protein SRSF3 in MK and platelets, it was observed that MKs with high ploidy and large cytoplasm produce platelets and also negatively regulate HSC function; their absence resulted in an elevated HSC pool and severe thrombocytopenia [13 ▪ ].…”

Section: Hematopoietic Niche Regulating Megakaryocytesmentioning

confidence: 99%

“…The 'hematopoietic stem cell' (HSC) niche supporting MKs also present with high ploidy and are the second largest subset in the bone marrow. They also highly express Igf1 and Pf4 [12,13 can be distinguished by their low ploidy state and smaller size, ($7.4 mm). In addition, they express several transcription factors important for granulocyte and monocyte development, such as Spi1, Cebpd, Cebpe, Irf5, and Irf8 [14].…”

Section: Introduction: Megakaryocyte Heterogeneity and Plasticitymentioning

confidence: 99%

“…The ‘hematopoietic stem cell’ (HSC) niche supporting MKs also present with high ploidy and are the second largest subset in the bone marrow. They also highly express Igf1 and Pf4 [12,13 ▪ ], two cytokines involved in the regulation of HSCs, as well as WNT signaling genes ( Wnt3a, Wnt4, Dkk1 , and Dkk2) . In contrast, ‘immune’ MKs can be distinguished by their low ploidy state and smaller size, (∼7.4 μm).…”

Section: Introduction: Megakaryocyte Heterogeneity and Plasticitymentioning

confidence: 99%

See 1 more Smart Citation

The many faces of the megakaryocytes and their biological implications

Guo,

Machlus,

Camacho

2023

Current Opinion in Hematology

View full text Add to dashboard Cite

Purpose of review Single-cell RNA sequencing studies have revealed transcriptional heterogeneity within the megakaryocytic lineage and the identified unique subsets. In this review, we discuss the functional and phenotypic plasticity of these subpopulations as well as the impacts on health and disease. Recent findings Megakaryocytes (MKs) can be transcriptionally categorized into platelet generating, niche supporting, immune, and cycling cells, which are distinguished by their unique gene expression patterns and cellular markers. Additionally, a significant population of these cells has been established to reside in the nonhematopoietic tissues and they display enhanced immune-related characteristics. Combined with the location in which the megakaryocytes exist, these cells can play unique roles dictated by their current environment and biological needs, including responding to changes in pathogen exposure. Summary Advances in megakaryocyte research has elucidated the existence of multiple subpopulations of MKs that serve different functions. These subpopulations implicate a greater potential for MKs to be regulators of health and suggest new avenues for treatments and therapies in related diseases.

show abstract

Pf450 High Ploidy Large Cytoplasmic Megakaryocytes: Key Negative Regulators of Hematopoietic Stem Cells and Essential for Platelet Production

Cited by 6 publications

References 0 publications

Single Cell Resolution Spatial Mapping of Human Hematopoiesis Reveals Aging-Associated Topographic Remodeling

Single Cell Resolution Spatial Mapping of Human Hematopoiesis Reveals Aging-Associated Topographic Remodeling

An age-specific platelet differentiation path from hematopoietic stem cells contributes to exacerbated thrombosis

The many faces of the megakaryocytes and their biological implications

Contact Info

Product

Resources

About