Inhibition of MEIS1 allows expansion of hematopoietic stem cells

Hematopoietic stem cells (HSCs) are characterized by high capacity of self-renewing and differentiation to all blood lineages. HSCs have been generally used in HSC transplantation (HSCT) to treat the hematological diseases due to their self-renew and differentiation capacities. There are ex vivo studies carried out to expand HSC to improve HSCTs. We have been previously shown that deletion of HSC quiescence-related gene Meis1 induces the expansion of HSCs. Targeting Meis1 levels in HSCs appears as a plausible therapeutical target on stem cell expansion technologies. We aimed the development of HSC technologies through inhibition of Meis1 in this study. Therefore, we employed in silico and in vitro strategies. In silico screening of over a million small molecules against crystalised Meis1 homeodomain was carried out by Autodock Vina – PaDel Adv platform. In vitro activity of hits were analyzed with Meis1 luciferase reporter assays, gene target analysis by RT-PCR and flow cytometric profiling of HSCs ex vivo and in vivo. We have shown that inhibition of Meis1 leads to downregulation of Meis1 target genes, downregulation of CDKIs, and expansion of murine and human HSCs. These findings suggest that inhibition of Meis1 could provide important contributions to stem cell expansion technologies needed on stem cell transplantation and decrease dependency to the cytokines used for stem cell expansion.