Chemotherapy-Induced Bone Defects Stem from Skeletal Progenitor Dysfunction
Notice bibliographique
Résumé
Combination chemotherapy has markedly improved the survival rates among acute lymphoblastic (ALL) leukemia patients (Hunger & Mulligan, NEJM 2015). However, treatment-related long-term morbidities, including skeletal defects, present a significant clinical challenge. Cancer survivors frequently suffer from osteoporosis, increased fracture risk, and, in pediatric cases, height deficit, profoundly impacting their quality of life (Vandecruys et al., J. Pediatr. 2013). The development of interventions to preserve bone is impeded by an incomplete understanding of molecular mechanisms underlying long-term bone toxicity mediated by chemotherapy. Skeletal integrity is maintained by active osteoblasts, which originate from bone marrow (BM) mesenchymal stem and progenitor cells (MSPCs) (Zhou et al., Cell Stem Cell 2014). We previously showed that chemotherapy can induce significant transcriptional reprogramming in MSPCs, leading to a reduction in their osteogenic potential (Tikhonova & Dolgalev et al., Nature 2019). Nevertheless, it remains unclear whether these stress-induced alterations in MSPCs can persist over time and contribute to permanent bone defects. To examine the long-term impact of chemotherapy on MSPCs, we treated mice with doxorubicin (DOX), an anthracycline prescribed in ALL induction therapy. Mice receiving DOX treatment exhibited short stature, trabecular bone loss, and diminished bone mineral density 20 weeks post-treatment, indicating that DOX alone was adequate to induce long-term skeletal defects in mice. Flow cytometry analysis revealed a marked reduction in the frequency of osteogenic MSPCs in DOX-treated animals. Moreover, we found that in vivo DOX treatment led to MSPC dysfunction, as indicated by loss of ex vivo colony-forming capacity and osteogenic differentiation potential. To map MSPC fate in vivo, we conducted lineage tracing experiments using Lepr-tdT;2.3Col-GFP reporter model. Our results revealed a loss of MSPC-derived osteoblasts in DOX-treated animals. Collectively, these findings indicate the loss of functional MSPCs and a shift in MSPC lineage priming following DOX treatment. Next, we performed bulk RNA sequencing to investigate DOX-mediated molecular changes in MSPCs. Our analysis showed a decrease in osteogenesis-associated pathways and an upregulation of genes associated with DNA damage response and adipogenesis in MSPCs following DOX treatment. Interestingly, we found upregulation of pathways associated with inflammatory response. It has been shown that chronic inflammation shapes function and fate of stem cells (Matatall et al. Cell Rep. 2016). Thus, this finding offers a critical insight into the mechanisms underlying DOX-mediated MSPC dysfunction. Next, to explore the transcriptional heterogeneity of the BM microenvironment, we performed unbiased single-cell RNA sequencing on BM stromal and endothelial populations. We found an enrichment of adipo-primed MSPCs, a loss of osteo-primed MSPCs, as well as a decrease in genes associated with osteogenesis in both MSPC subsets. We also noted a decrease in the frequency of arteriolar vascular endothelial cells, which are typically maintained by osteo-primed MSPCs (Shen et al. Nature 2021). Moreover, we curated transcription factor (TF) regulon signatures on our dataset with SCENIC (Aibar et al. Nat. Med. 2017) and found that DOX-treated mice had a significant decrease in the activity of TFs promoting osteogenesis. Finally, RNA velocity-based lineage trajectory inference (Bergen et al. Nat. Biotechnol. 2020) revealed impaired transition of MSPCs towards the osteogenic lineage. These results indicate that the DOX-mediated MSPC dysfunction is caused by long-term transcriptional rewiring of MSPCs. Collectively, our results demonstrate that DOX disrupts MSPC differentiation trajectories through permanent molecular reprogramming, resulting in impaired osteogenesis and enduring skeletal defects. Our current work aims to investigate the role of inflammation in DOX-mediated MSPC dysfunction. We anticipate that when completed, this study will elucidate the mechanisms underlying chemotherapy-induced osteotoxicity and facilitate the development of strategies to enhance skeletal health in cancer survivors.
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 | 0,001 | 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) | 0,002 | 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 ».