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A unique microenvironment in the developing liver supports the expansion of megakaryocyte progenitors.

ABSTRACT: The fetal liver is the site of a major expansion of the hematopoietic stem cell (HSC) pool and is also a privileged organ to study megakaryocyte progenitor differentiation. We identified in the mouse fetal liver at day 13.5 a discrete stromal cell population harboring a CD45^-TER119^-CD31^-CD51⁺VCAM-1⁺PDGFRα^- (V⁺P^-) phenotype that lacked colony-forming unit fibroblast activity and harbored an hepatocyte progenitor signature. This previously undescribed V⁺P^- population efficiently supported megakaryocyte production from mouse bone marrow HSC and human peripheral blood HSC-myeloid progenitors cultured in the presence of limited cytokine concentrations. Megakaryocytes obtained in V⁺P^- cocultures were polyploid, positive for CD41/CD42c, and efficiently produced proplatelets. Megakaryocyte production appeared to be mediated by an expansion of the progenitor compartment through HSC-stromal cell contact. In conclusion, the fetal liver contains a unique cellular microenvironment that could represent a platform for the discovery of regulators of megakaryopoiesis.

SUBMITTER: Brouard N

PROVIDER: S-EPMC5728093 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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A unique microenvironment in the developing liver supports the expansion of megakaryocyte progenitors.

Brouard Nathalie N Jost Camille C Matthias Nadine N Albrecht Camille C Egard Sébastien S Gandhi Poojabahen P Strassel Catherine C Inoue Tomoko T Sugiyama Daisuke D Simmons Paul J PJ Gachet Christian C Lanza Francois F

Blood advances 20170926 21

The fetal liver is the site of a major expansion of the hematopoietic stem cell (HSC) pool and is also a privileged organ to study megakaryocyte progenitor differentiation. We identified in the mouse fetal liver at day 13.5 a discrete stromal cell population harboring a CD45-TER119-CD31-CD51+VCAM-1+PDGFRα- (V+P-) phenotype that lacked colony-forming unit fibroblast activity and harbored an hepatocyte progenit ...[more]

PMID: 29296832

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Project description: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.

Dataset Information

A unique microenvironment in the developing liver supports the expansion of megakaryocyte progenitors.

Publications

A unique microenvironment in the developing liver supports the expansion of megakaryocyte progenitors.

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