Abstract PR07: MicroRNA-130a regulates hematopoietic stem cell self-renewal and erythroid differentiation
Notice bibliographique
Résumé
Abstract Hematopoietic homeostasis is tightly regulated by controlling the balance between quiescence, self-renewal, and lineage-commitment of hematopoietic stem cells (HSCs). Deregulation of these processes and aberrant acquisition of stem cell-like properties is believed to be central to the pathogenesis of hematologic malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, little is known about the molecular networks maintaining the stem cell state and the epigenetic and post-transcriptional regulation of determinants that control these programs. MicroRNAs (miRNAs) represent a large class of post-transcriptional regulators that mediate repression of multiple target mRNAs. We have previously shown that miR-126 and miR-125a are differentially expressed across the human hematopoietic hierarchy and function to control self-renewal and cell fate decisions by reinforcing gene expression programs in a developmental stage-specific manner (Lechman et al. Cell Stem Cell, 2012; Wojtowitz et al. Cell Stem Cell, 2016). To identify additional miRNA(s) that play a functional role in hematopoiesis, we performed an in vivo competitive repopulation screen in which candidate miRNAs were overexpressed (OE) in human CD34+CD38- umbilical cord blood (CB) cells and subsequently transplanted into immune-deficient mice for 24 weeks. miR-130a was shown to enhance long-term hematopoietic reconstitution and chosen for further investigation. At 12 and 24 weeks after transplantation, enforced miR-130a expression (including an mOrange-mO+ indicator) conferred a competitive advantage over untransduced CB cells demonstrated by increased CD45+ human chimerism in the injected femur (IF), bone marrow (BM), and spleen of recipient mice. miR-130 enforced expression (miR-130a OE) increased the proportion of mO+/hCD45+ cells by approximately 2- and 5-fold after 12 and 24 weeks of repopulation, respectively. miR-130a OE xenografts showed multilineage engraftment with increased myeloid lineage output and significantly enhanced erythroid development at the expense of B-lymphoid lineage output in BM and spleen of recipient mice. Detailed flow cytometry analysis of xenografts revealed accumulation of immature GlyA+/CD71+/CD36+ erythroid progenitors, suggesting a differentiation block at the polychromic erythroblast stage. Notably, miR-130a OE induced the expansion of CD34+CD38- Lin- compartment and increased proportion of CD34+CD38-CD90+CD45RA- immuno-phenotypic HSC. Secondary transplantation involving limiting dilution analysis revealed approximately a 10-fold increase in HSC frequency, consistent with a role of miR-130a in HSC self-renewal. The lineage potential of miR-130OE primitive cells was assessed in vitro using single-cell stromal-based myelo-erythroid differentiation assay. Enforced expression of miR-130a in human HSC and multipotent progenitors (MPP) resulted in the decreased frequency of unipotent myeloid output (M colonies) and increased multipotent output (M/E/Meg, E/Meg colonies), supporting a role of miR-130a in erythroid-megakaryocytic fate specification. Label-free semiquantitative proteomics and subsequent gene set enrichment pathway analysis (GSEA) were performed on miR-130a OE and control transduced CD34+ CB cells to elucidate molecular mechanism(s) of miR-130a function. We identified that miR-130a modulated pathways centered on translational regulation and chromatin modification. Together, our data suggest that miR-130a plays a role in the regulation of the HSC self-renewal and erythroid differentiation. Given that several studies showed aberrant expression of miR-130a in MDS and some AML subtypes, it is important to delineate the role of miR-130a in normal hematopoiesis to comprehend its potential contribution to the development of hematologic malignancies. This abstract is also being presented as Poster 40. Citation Format: Gabriela Krivdova, Eric R. Lechman, Erwin M. Schoof, Veronique Voisin, Olga I. Gan, Aaron Trotman-Grant, Karin G. Hermans, Gary D. Bader, John E. Dick. MicroRNA-130a regulates hematopoietic stem cell self-renewal and erythroid differentiation [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr PR07.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 ».