Heterogeneous Nuclear Ribonucleoprotein L is required for the survival and functional integrity of murine hematopoietic stem cells.

In mice, hematopoiesis originates from hematopoietic stem cells (HSC) that migrate from the aorta-gonad-mesonephros region (AGM) towards the fetal liver (FL) at embryonal stage 10.5 day post-coitus and later on, takes place in the bone marrow (BM) of adult mice1,2. In both FL and BM, HSCs possess a unique self-renewal capacity and the potential to generate all mature blood and immune cells of an organism throughout its lifetime3,4,5. The commitment of HSCs to differentiate into specific cell lineages is tightly regulated and starts with the formation of multipotent progenitors (MPPs) that have a reduced self-renewal capacity and are already restricted in their multilineage potential6,7. The earliest precursors that emerge from MPPs still have both myeloid and lymphoid potential and are called LMPPs8,9. HSCs reside in the BM or the FL and are part of the Lin−Sca1+cKit+ (LSK) subset. They can be further defined by the expression of the markers CD150 and CD48 (i.e. HSCs are Lin−Sca1+cKit+CD150+CD48−)10,11,12,13. While most HSCs in adult mice are in a quiescent stage, embryonic HSCs are proliferating to generate the adult pool of stem cells5,14,15. Many transcription factors including Runx1, Gfi1, Gfi1b, GATA2, SCL and Notch1 have been identified as important regulators of lineage commitment as well as HSCs quiescence and survival16,17,18,19,20. However, the role that mRNA processing factors may have for HSCs remains unexplored, even though they are known to control gene expression at the transcriptional and posttranscriptional level21,22. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) is an RNA processing factor and an RNA-binding protein that has been identified to regulate alternative splicing by binding exonic splicing silencers elements (ESS) resulting in exon exclusion from the mature mRNA23,24,25. To investigate the role of hnRNP L in HSC function and hematopoietic differentiation, we have generated conditional hnRNP L knockout mice. Here, we present evidence that hnRNP L is essential for the survival and functional integrity of HSCs since ablation of this factor is incompatible with proper hematopoietic differentiation and causes premature and accelerated death in hnRNP L deficient animals. In particular, we report that hnRNP L deficient HSCs show increased mitochondrial stress and initiate both p53- and caspase-dependent cell death pathways.