Regulation of Oxidative Stress by ATM Is Required for the Self-Renewal of Haematopoietic Stem Cells.
Notice bibliographique
Résumé
Abstract It has been hypothesized that a signaling pathway for regulating aging and longevity may be involved in stem cell functions. To address the hypothesis we investigate roles of molecules that regulate aging on self-renewal capacity of HSC. Ataxia telangiectasia (A-T) is an autosomal recessive disorder caused by mutational inactivation of the ATM. ATM has a central role in maintenance of genomic stability via regulating cell cycle checkpoint in response to DNA damage, stability of telomere and oxidative stress. A-T patients display variety of sympotoms including high incidence of lymphoma and premature aging. In this study we investigated the effects of ATM deficiency on the hematopoietic system. ATM−/− mice have normal numbers of peripheral blood cells and colony-forming cells in the bone marrow (BM) at the age of 8 weeks. A frequency of KSL in the ATM−/− BM was similar to that of wild-type mice. However, the number of colony-forming cells derived from ATM−/− KSL cells after 6 weeks co-culture of stromal cells was significantly decreased. To directly assess a repopulating ability of the HSC in vivo, we performed a competitive reconstitution assay with congenic mice. Short-term (4-weeks) repopulation was not affected. However, there were dramatically fewer hematopoietic cells derived from ATM−/− BM at 16 weeks post-transplant, indicating that ATM has an essential role in the self-renewal of adult HSCs, but is not required for the differentiation or proliferation of hematopoietic progenitor cells. We next evaluated the effects of ATM deficiency on hematopoiesis in older mice. All ATM−/− mice older than 20 weeks exhibited a progressive pancytopenia with hypocellularity in bone marrow. The numbers of myeloid and erythroid precursors among ATM−/− BM MNCs were markedly decreased, KSL cells had disappeared, and co-culture on stromal cells showed that ATM−/− cells were no longer able to form any colonies after 2 weeks of culture. Taken together, our data indicate that chronic ATM deficiency in vivo results in progressive multi-lineage BM failure due to defective maintenance of the adult HSC pool. ATM is involved in oxidative defense, and the loss of ATM results in oxidative damage in several tissues. To elucidate the mechanism underlying the regulation of the HSC pool by ATM, we next evaluated ROS generation in HSC, and were able to demonstrate that the intracellular concentration of radical oxygen was higher in KSL cells from ATM−/− mice than from WT animals. Two members of CDK inhibitors, p16 and p19, were highly elevated in ATM−/− KSL cells after 2 days in vitro incubation with cytokines. Treatment with the permeant thiol N-acetylcysteine (NAC) abrogated the upregulation of p16 and p19 expression and BM failure corresponding to decrease in the level of intracellular ROS. The numbers of colonies formed from ATM−/− HSCs were restored to near-WT levels by treatment with either NAC or catalase in long term culture. Furthermore we found that NAC treatment of ATM−/− mice dramatically restored the repopulation capacity comparable to that of the WT. We conclude that self-renewal capacity of HSCs depends on ATM-mediated inhibition of oxidative stress. Our data support a model in which master regulator molecules govern the disparate processes of stem cell self-renewal, normal aging and tumor development.
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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) | 0,002 | 0,000 |
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 ».