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

• Published in: Scientific reports Vol. 6; no. 1; p. 27379
• Main Authors: Gaudreau, Marie-Claude, Grapton, Damien, Helness, Anne, Vadnais, Charles, Fraszczak, Jennifer, Shooshtarizadeh, Peiman, Wilhelm, Brian, Robert, François, Heyd, Florian, Möröy, Tarik
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-06-2016; Nature Publishing Group
• Subjects: 13/100; 13/2; 13/31; 38/91; 631/532/1542; 631/80/82/23; 64/60; Ablation; Animals; Antibodies; Apoptosis; Apoptosis - genetics; Blood; Cell death; Cell Survival - physiology; Hematopoietic Stem Cells - cytology; Heterogeneous-Nuclear Ribonucleoprotein L - genetics; Heterogeneous-Nuclear Ribonucleoprotein L - physiology; Humanities and Social Sciences; Iodides; Mice; Mice, Knockout; Mortality; multidisciplinary; Real-Time Polymerase Chain Reaction; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Science; Science (multidisciplinary); Stem cells; Stress, Physiological; Survival; Transplants & implants; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep27379

The proliferation and survival of hematopoietic stem cells (HSCs) has to be strictly coordinated to ensure the timely production of all blood cells. Here we report that the splice factor and RNA binding protein hnRNP L (heterogeneous nuclear ribonucleoprotein L) is required for hematopoiesis, since its genetic ablation in mice reduces almost all blood cell lineages and causes premature death of the animals. In agreement with this, we observed that hnRNP L deficient HSCs lack both the ability to self-renew and foster hematopoietic differentiation in transplanted hosts. They also display mitochondrial dysfunction, elevated levels of γH2AX, are Annexin V positive and incorporate propidium iodide indicating that they undergo cell death. Lin
-
c-Kit
+
fetal liver cells from hnRNP L deficient mice show high p53 protein levels and up-regulation of p53 target genes. In addition, cells lacking hnRNP L up-regulated the expression of the death receptors
TrailR2
and
CD95/Fas
and show Caspase-3, Caspase-8 and Parp cleavage. Treatment with the pan-caspase inhibitor Z-VAD-fmk, but not the deletion of p53, restored cell survival in hnRNP L deficient cells. Our data suggest that hnRNP L is critical for the survival and functional integrity of HSCs by restricting the activation of caspase-dependent death receptor pathways.