Expression of plasma membrane receptor genes during megakaryocyte development

Sun, Shaoli; Wang, Wenjing; Latchman, Yvette; Gao, Dayong; Aronow, Bruce J.; Reems, Jo‐Anna

doi:10.1152/physiolgenomics.00056.2012

Cited by 22 publications

(19 citation statements)

References 38 publications

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“…Because Population 1 remained negatively defined among CD34 + 38+ hematopoietic progenitors (Lin- CD34 + CD38 + CD123- CD45RA-CD71- CD41-), we sought to determine whether our immunophenotyping strategy for this population could be further refined by including additional surface antigens from our gene expression profiling panel that were not part of the original FACS panel. CD44, an adhesion molecule expressed by MEP and early erythroid and megakaryocytic progenitors that is downregulated during their differentiation and maturation [ 32 , 33 ] emerged as the most prominent positive identifier of Population 1 by gene expression, with a mean expression level fivefold higher than the other two populations ( P <0.0001, Fig. 4b ).…”

Section: Resultsmentioning

confidence: 99%

Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways

et al. 2016

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BackgroundRecent advances in single-cell techniques have provided the opportunity to finely dissect cellular heterogeneity within populations previously defined by “bulk” assays and to uncover rare cell types. In human hematopoiesis, megakaryocytes and erythroid cells differentiate from a shared precursor, the megakaryocyte-erythroid progenitor (MEP), which remains poorly defined.ResultsTo clarify the cellular pathway in erythro-megakaryocyte differentiation, we correlate the surface immunophenotype, transcriptional profile, and differentiation potential of individual MEP cells. Highly purified, single MEP cells were analyzed using index fluorescence-activated cell sorting and parallel targeted transcriptional profiling of the same cells was performed using a specifically designed panel of genes. Differentiation potential was tested in novel, single-cell differentiation assays. Our results demonstrate that immunophenotypic MEP comprise three distinct subpopulations: “Pre-MEP,” enriched for erythroid/megakaryocyte progenitors but with residual myeloid differentiation capacity; “E-MEP,” strongly biased towards erythroid differentiation; and “MK-MEP,” a previously undescribed, rare population of cells that are bipotent but primarily generate megakaryocytic progeny. Therefore, conventionally defined MEP are a mixed population, as a minority give rise to mixed-lineage colonies while the majority of cells are transcriptionally primed to generate exclusively single-lineage output.ConclusionsOur study clarifies the cellular hierarchy in human megakaryocyte/erythroid lineage commitment and highlights the importance of using a combination of single-cell approaches to dissect cellular heterogeneity and identify rare cell types within a population. We present a novel immunophenotyping strategy that enables the prospective identification of specific intermediate progenitor populations in erythro-megakaryopoiesis, allowing for in-depth study of disorders including inherited cytopenias, myeloproliferative disorders, and erythromegakaryocytic leukemias.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-0939-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways

et al. 2016

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“…This is in line with previous studies showing that T-cell lymphoproliferation is dominant over megakaryocytic expansion in bone marrow transplantation assays. 9,41 Although recent studies have shown that IL-9 and IL-21 both signal through gc chain and Jak1 tyrosine kinase to regulate megakaryopoiesis, [53][54][55][56] the cytokine receptor on which activated JAK3 is bound in megakaryocytes remains to be identified. Of note, the importance of the Jak3-mutant signaling intensity may also apply to other lineages.…”

Section: Discussionmentioning

confidence: 99%

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

et al. 2018

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JAK3-activating mutations are commonly seen in chronic or acute hematologic malignancies affecting the myeloid, megakaryocytic, lymphoid, and natural killer (NK) cell compartment. Overexpression models of mutant JAK3 or pharmacologic inhibition of its kinase activity have highlighted the role that these constitutively activated mutants play in the T-cell, NK cell, and megakaryocytic lineages, but to date, the functional impact of JAK3 mutations at an endogenous level remains unknown. Here, we report a JAK3 knockin mouse model and demonstrate that activated JAK3 leads to a progressive and dose-dependent expansion of CD8 T cells in the periphery before colonization of the bone marrow. This phenotype is dependent on the γc chain of cytokine receptors and presents several features of the human leukemic form of cutaneous T-cell lymphoma (L-CTCL), including skin involvements. We also showed that the JAK3-positive malignant cells are transplantable and phenotypically heterogeneous in bone marrow transplantation assays. Interestingly, we revealed that activated JAK3 functionally cooperates with partial trisomy 21 in vivo to enhance the L-CTCL phenotype, ultimately leading to a lethal and fully penetrant disorder. Finally, we assessed the efficacy of JAK3 inhibition and showed that CTCL JAK3-positive T cells are sensitive to tofacitinib, which provides additional preclinical insights into the use of JAK3 inhibitors in these disorders. Altogether, this JAK3 knockin model is a relevant new tool for testing the efficacy of JAK inhibitors in JAK3-related hematopoietic malignancies.

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“…ajp.amjpathol.org -The American Journal of Pathology CD44 are differentially expressed during MK development, with RHAMM increasing sixfold and CD44 decreasing during maturation. 63 Regulation of p38 modulates MK differentiation and maturation.…”

Section: Hyal-2 and Efficient Thrombopoiesismentioning

confidence: 99%

Hyaluronan Depolymerization by Megakaryocyte Hyaluronidase-2 Is Required for Thrombopoiesis

Petrey

Obery

Kessler

et al. 2016

The American Journal of Pathology

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Hyaluronan is the predominant glycosaminoglycan component of the extracellular matrix with an emerging role in hematopoiesis. Modulation of hyaluronan polymer size is responsible for its control over cellular functions, and the balance of hyaluronan synthesis and degradation determines its molecular size. Although two active somatic hyaluronidases are expressed in mammals, only deficiency in hyaluronidase-2 (Hyal-2) results in thrombocytopenia of unknown mechanism. Our results reveal that Hyal-2 knockout mice accumulate hyaluronan within their bone marrow and within megakaryocytes, the cells responsible for platelet generation. Proplatelet formation by Hyal-2 knockout megakaryocytes was disrupted because of abnormal formation of the demarcation membrane system, which was dilated and poorly developed. Importantly, peptide-mediated delivery of exogenous hyaluronidase rescued deficient proplatelet formation in murine and human megakaryocytes lacking Hyal-2. Together, our data uncover a previously unsuspected mechanism of how hyaluronan and Hyal-2 control platelet generation.

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Expression of plasma membrane receptor genes during megakaryocyte development

Cited by 22 publications

References 38 publications

Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways

Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

Hyaluronan Depolymerization by Megakaryocyte Hyaluronidase-2 Is Required for Thrombopoiesis

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