AHR:IKAROS Interaction Promotes Platelet Biogenesis in Response to SR1

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.

Ricolinostat promotes the generation of megakaryocyte progenitors from human hematopoietic stem and progenitor cells

“…Improving the efficiency of MkP or MK precursor generation from HSPCs is a critical step in inducing functional MK and platelet production in vitro. Previous studies indicated that an MK precursor population with strong MK differentiation potential can be enriched by subculturing the cells with bone marrow mesenchymal stromal cells or StemRegenin 1 treatment [ 37 , 38 ]. It remains challenging to increase the committed differentiation of MkPs from HSPCs using new inducing agents.…”