IFN-γ drives long-term bone marrow niche dysfunction following chemotherapy
Notice bibliographique
Résumé
Abstract Since their introduction in the 1960s, chemotherapy agents have remained a cornerstone of treatment for hematopoietic malignancies. However, their non-specific cytotoxic effects extend beyond malignant cells, inflicting collateral damage on healthy tissues. Hematopoiesis is supported by the bone marrow (BM) microenvironment, where mesenchymal stromal cells (MSCs) and vascular endothelial cells (ECs) provide critical factors for hematopoietic stem cell (HSC) quiescence, self-renewal, and differentiation. Clinical observations indicate that leukemia patients exposed to high-dose chemotherapy retain a diminished hematopoietic progenitor pool years after transplantation, despite normalized peripheral blood counts, suggesting long-term impairment of the BM niche. Yet, the cellular and molecular mechanisms underlying this persistent dysfunction remain poorly understood. Here, we demonstrate that doxorubicin (DOX), a widely used anthracycline in treatment of leukemia, lymphoma and breast cancer, induces long-term remodeling of the BM niche. Mice administrated serial DOX treatment exhibited acute lymphopenia and expansion of hematopoietic progenitors. While mature hematopoietic populations were fully restored to baseline by 8 weeks (w), we observed a persistent increase in phenotypic HSCs, suggesting a sustained loss of HSC quiescence. Next, to specifically examine the impact of DOX on the hematopoietic supportive capacity of the BM niche, we transplanted HSCs into DOX or control-treated recipients. Sixteen weeks post-transplant, we observed diminished donor HSC pool in DOX-treated hosts, indicating impaired HSC maintenance by the BM niche. Single cell transcriptomics and functional assays revealed that DOX disrupts both stromal and vascular compartment of the BM niche. MSCs displayed reduced ex vivo colony forming capacity and impaired in vivo differentiation towards osteoblasts and adipocytes, leading to the accumulation of undifferentiated, dysfunctional MSCs 20w post-treatment. Consequently, DOX-treated mice showed pronounced trabecular loss, decreased skeletal mechanical strength and delayed fracture healing-features that align with bone complications observed in leukemia patients. In parallel, DOX led to depletion of arteriolar vessels and pericytes, which are essential for maintaining HSC quiescence and niche integrity. Collectively, these results indicate that DOX induced persistent remodeling of the BM microenvironment extends far beyond the treatment window. Singel cell transcriptomic analyses revealed sustained activation of inflammatory responses in MSCs and ECs 8w following DOX treatment, promoting investigation into the source of inflammation. Multiplex cytokine assays revealed increased interferon gamma (IFNγ) level in BM supernatant, but not serum, implicating localized inflammation. Flow cytometry analysis showed a significant increase in CD8+ T cell and an expansion of effector memory CD8+ T cells. Moreover, elevated IFNγ production was observed in CD8⁺ T cells from DOX-treated mice upon stimulation, indicating prior activation and increased effector function following DOX exposure. Notably, genetic ablation of IFNγ receptor or IFNγ blockade rescued DOX-induced vascular defects and restored MSC adipogenic differentiation. DOX-mediated bone loss was also partially mitigated in mice lacking IFNγ receptor. These results highlighted IFNγ signaling as a central driver of DOX-mediated niche dysfunction. Together, our data showed that DOX dismantles the cellular architecture of the HSC-supportive niche, replacing it with a chronically inflamed, structurally disordered environment. This dysfunctional niche compromises HSC maintenance, impairs skeletal integrity, and may underlie persistent hematopoietic deficits in cancer survivors. Targeting inflammatory mediators, such as IFNγ, presents a promising therapeutic strategy to preserve niche function, support tissue regeneration, and improve long-term outcomes following chemotherapy.
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) | 0,001 | 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 ».