MicroRNA-146a disrupts hematopoietic differentiation and survival

Objective. MicroRNAs (miRNAs) are short noncoding RNAs capable of exerting dramatic effects by postranscriptionally regulating numerous messenger RNA targets. Toll-like receptor-4 (TLR-4) activation by lipopolysaccharide (LPS) induces the expression of three miRNAs in myeloid cells. The aim of this study was to investigate the in vivo consequences of expressing one of the LPS-induced miRNA, miR-146a, in bone marrow cells. Material and Methods. The role of miR-146a in hematopoiesis was investigated by using retroviral infection and overexpression of miR-146a in mouse hematopoietic stem/progenitor cells, followed by bone marrow transplantations. Results. miR-146a is mainly expressed in primitive hematopoietic stem cells and T lymphocytes. Overexpression of miR-146a in hematopoietic stem cells, followed by bone marrow transplantation, resulted in a transient myeloid expansion, decreased erythropoiesis, and impaired lymphopoiesis in select anatomical locations. Enforced expression of miR-146a also impaired bone marrow reconstitution in recipient mice and reduced survival of hematopoietic stem cells. Conclusions. Our results indicate that miR-146a, an LPS-induced miRNA, regulates multiple aspects of hematopoietic differentiation and survival. Furthermore, the consequences of miR-146a expression in hematopoietic cells mimics some of the reported effects with acute LPS exposure. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.