Abstract
In vitro, the differentiation of megakaryocytes (MKs) is improved by aryl-hydrocarbon receptor (AHR) antagonists such as StemRegenin 1 (SR1), an effect physiologically recapitulated by the presence of stromal mesenchymal cells (MSC). This inhibition promotes the amplification of a CD34+CD41low population able to mature as MKs with a high capacity for platelet production. In this short report, we showed that the emergence of the thrombocytogenic precursors and the enhancement of platelet production triggered by SR1 involved IKAROS. The downregulation/inhibition of IKAROS (shRNA or lenalidomide) significantly reduced the emergence of SR1-induced thrombocytogenic population, suggesting a crosstalk between AHR and IKAROS. Interestingly, using a proximity ligation assay, we could demonstrate a physical interaction between AHR and IKAROS. This interaction was also observed in the megakaryocytic cells differentiated in the presence of MSCs. In conclusion, our study revealed a previously unknown AHR/ IKAROS -dependent pathway which prompted the expansion of the thrombocytogenic precursors. This AHR- IKAROS dependent checkpoint controlling MK maturation opens new perspectives to platelet production engineering.
Highlights
Blood platelets are efficiently generated from bone marrow megakaryocytes (MKs) where each MK is predicted to produce 2000–3000 platelets
Megakaryopoiesis (MKP) is a hierarchized and complex process where hematopoietic stem cells (HSCs) differentiate to give rise to megakaryocytic progenitors, which will differentiate into mature MKs capable of extending cytoplasmic extensions into the sinusoid vessel to release platelets under flow [2]
We reported that the Aryl-Hydrocarbon Receptor (AHR) antagonist, StemRegenin 1 (SR1), favors the expansion in culture at day 10 of a specific population of progenitors, phenotypically defined as CD34+ CD41low cells, empowered with an enhanced potential to generate mature MKs allowing us to obtain a yield of 50–100 platelets/CD34 progenitor [6]
Summary
Blood platelets are efficiently generated from bone marrow megakaryocytes (MKs) where each MK is predicted to produce 2000–3000 platelets. We reported that the Aryl-Hydrocarbon Receptor (AHR) antagonist, StemRegenin 1 (SR1), favors the expansion in culture at day 10 of a specific population of progenitors, phenotypically defined as CD34+ CD41low cells, empowered with an enhanced potential to generate mature MKs allowing us to obtain a yield of 50–100 platelets/CD34 progenitor [6]. At this point the AHR-dependent mechanisms involved in specifying this remarkable population remain unresolved
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