Heterogenous Nuclear Ribonucleoprotein L (hnRNPL) Is Required for the Functional Integrity of Hematopoietic Stem Cells.
Notice bibliographique
Résumé
Abstract Abstract 1486 Poster Board I-509 Hematopoietic differentiation has to be tightly regulated since uncontrolled or exaggerated development of blood cells may lead to the development of leukemia or autoimmune diseases. Many mechanisms exist to control hematopoiesis on a molecular level, including the regulation of transcription, which has been intensely studied. However, new evidence suggests the process of alternative splicing to be an important regulator of the maturation and activation of blood- and immune effector cells. One of the factors that has been identified as a potential regulator of the immune response and controls alternative splicing is “heterogenous nuclear ribonucleoprotein L” (hnRNP L). This factor affects among others the alternative splicing of the CD45 gene, which encodes the major tyrosine phosphatase expressed on all hematopoietic cells. To investigate the biological role of hnRNP L as a regulator of alternative splicing in hematopoiesis, we have generated conditional hnRNP L knockout (KO) mice carrying floxed alleles that can be deleted by co expression of Cre recombinase. Both the inducible MxCre transgene or Vav-Cre transgene, which is active in all hematopoietic cells were introduced into hnRNP Lfl/fl mice. We found that the conditional deletion of hnRNP L by the Vav Cre transgene led to early mortality before birth (at stage E17.5) and flow cytometric analysis of fetal liver of hnRNP Lfl/fl, Vav-Cre mice or bone marrow from pIpC induced hnRNP Lfl/fl Mx-Cre mice showed a deficit in erythrocyte maturation. In addition, fetal thymi from hnRNP Lfl/fl X Vav-Cre mice were severely reduced in cellularity and showed disturbed T cell maturation. Moreover, the deletion of hnRNP L results in reduced numbers of Lin−Sca1+ckit+ (LSK) cells, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs) and megakaryocyte-erythrocyte progenitors (MEPs). Strikingly, while most of the progenitors and the short-term hematopoietic stem cells (HSCs) were affected by the deletion of hnRNP L, the population of long term HSCs was not reduced. We found a high percentage of Annexin V positive cells in the LSK population suggesting that the loss of progenitors and short term HSCs in hnRNP L deficient mice is due to an accelerated cell death. To test whether stem cells lacking hnRNP L were still functional, we sorted Lin−Sca1+ckit+ (LSK) cells and cultured them on either methylcellulose or the feeder cell lines OP9 and OP9-DL1. The co-culture with OP9 or OP9-DL1 cells demonstrated that hnRNP L−/− LSK cells had lost their potential to differentiate into B and T lymphocytes. Similarly, hnRNP L deficient LSK cells were unable to give rise to lymphoid, myeloid or erythroid colonies on methylcellulose. This suggests that hnRNP L is required to maintain not only the numbers of hematopoietic stem cells, but also their ability for multilineage differentiation. We conclude that the regulation of alternative splicing is an essential component of the regulatory network required to maintain hematopoietic differentiation and the functional integrity of hematopoietic stem cells. Disclosures: No relevant conflicts of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,002 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».