Aryl hydrocarbon receptor–dependent enrichment of a megakaryocytic precursor with a high potential to produce proplatelets

Abstract

International audienceThe mechanisms regulating megakaryopoiesis and platelet production (thrombopoiesis) are still incompletely understood. Identification of a progenitor with enhanced thrombopoietic capacity would be useful to decipher these mechanisms and to improve our capacity to produce platelets in vitro. Differentiation of peripheral blood CD34(+) cells in the presence of bone marrow-human mesenchymal stromal cells (MSC) enhanced the production of proplatelet-bearing megakaryocytes (MK) and platelet-like elements. This was accompanied by enrichment in a MK precursor population exhibiting an intermediate level of CD41 positivity while maintaining its expression of CD34. Following sorting and sub-culture with MSC, this CD34(+)CD41(low) population was able to efficiently generate proplatelet-bearing MK and platelet-like particles. Similarly, SR1, an antagonist of the aryl hydrocarbon receptor (AhR) transcription factor known to maintain CD34 expression of progenitor cells, led to an enriched CD34(+)CD41(low) fraction and to an increased capacity to generate proplatelet-producing MK and platelet-like elements ultrastructurally and functionally similar to circulating platelets. The effect of MSC, like that of SR1, appeared to be mediated by an AhR-dependent mechanism since both culture conditions resulted in repression of its downstream effector CYP1B1. This newly described isolation of a precursor exhibiting strong MK potential could be exploited to study normal and abnormal thrombopoiesis and for in vitro platelet productio

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

“…Some studies suggest that contact with stromal cell precursors negatively controls megakaryocytic differentiation of the human hematopoietic cell line K562 3,4 or human CD34 progenitors, 5,6 whereas other studies suggest that stromal cells support or enhance megakaryopoiesis. [7][8][9] This apparent contradiction may reside in differences in experimental design and in the complexity of the processes involved in the generation of megakaryocytes (MKs) from HSCs. Indeed, MKs are generated from HSCs through multiple steps of committed MK progenitors, including a bipotent megakaryocytic erythroid progenitor (MEP), leading to the production of a unipotent MK precursor, which will then mature into large polyploid MKs that will extend proplatelets in the circulation.…”

Umbilical Cord Blood Hematopoietic Stem and Progenitor Cell Expansion for Therapeutic Use

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