Mechanical Suppression of Microgravity-Induced Chondrocyte Hypertrophy in Engineered Human Cartilage
Notice bibliographique
Résumé
Articular cartilage (AC) of the knee exists under a low oxygen and mechanically active environment. Mechanical unloading conditions of spaceflight microgravity pose a risk for astronauts to develop knee osteoarthritis-like pathology, which culminates in AC atrophy and breakdown, joint space narrowing, subchondral bone thickening, and the formation of bone spurs. Mesenchymal stem cells (MSC) are a promising cell source for AC replacement given their potential to form AC precursor cells – chondrocytes, but current protocols can lead to undesirable hypertrophic differentiation that progresses to bone through the process of endochondral ossification when implanted in vivo. We have previously found that combining low oxygen and mechanical loading (mechano-hypoxia conditioning) during cartilage development from human bone marrow (hBM) derived-MSC under gravity loading conditions can reduce OA-like molecular characteristics. This research explored the treatment of mechano-hypoxia conditioning during chondrogenic stimulation of MSC under simulated microgravity (SMG) as a methodology to produce stable chondrocytes without the propensity to form bone. This was explored through the following objectives: 1. Determine the effect of mechano-hypoxia conditioning on chondrogenically stimulated MSC under SMG. 2. Determine if mechano-hypoxia-conditioned tissue-engineered cartilage from MSC resists bone formation after implantation in vivo. To achieve these objectives, hBM MSC sourced from four male (ages 25-51) and four female (ages 19-41) donors were isolated, expanded, and chondrogenically induced to form engineered cartilage models. The engineered cartilage models were subjected to static (gravity) conditions, SMG for 3 weeks, SMG for 6 weeks, and SMG for 3 weeks + dynamic compression (DC) respectively. SMG was applied to the constructs by culturing in a rotatory wall vessel bioreactor for the specified time. At the experimental endpoint, tissue constructs were randomly distributed for downstream analyses including gene expression, mechanical tests, biochemical assays for extracellular matrix, histology, and subcutaneous implantation in mice following University of Alberta animal use protocols. After 5 weeks, the implanted tissue was retrieved and imaged via micro-CT, micro-X-ray fluorescent imaging for biomineralization and scanning electron microscope (SEM) imaging for the structure and composition of calcification. Data from this study shows that Mechano-hypoxia conditioning significantly reduced the heightened expression of collagen X induced by SMG, validating this conditioning method as a countermeasure to microgravity-induced chondrocyte hypertrophy. Additionally, Matrix gla protein (MGP), a potent inhibitor of bone formation, was significantly upregulated by mechano-hypoxia conditioning. This increase was found to be correlated with a significant resistance to bone formation in vivo, measured through micro-CT analysis. This data suggests that mechano-hypoxia conditioning has the potential to counteract osteoarthritic characteristics induced in cartilage from SMG and lends insight into the mechanisms involved in the process of mechanosignalling for osteoarthritis and new areas of drug discovery research. The outcome of this experiment will advance our understanding of the molecular processes of cartilage breakdown in microgravity and avenues for prevention.
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 | 0,000 |
| 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 ».