The Glial Response to Focused Ultrasound-mediated Permeabilization of the Blood-brain Barrier: Evaluating the Potential Contribution of Microglia and Astrocytes to Pathology and Regeneration
Notice bibliographique
Résumé
Focused ultrasound in the presence of intravenous microbubbles (FUS) facilitates the non-invasive temporary permeabilization of the blood-brain barrier (BBB) for delivering therapeutics to the brain. FUS-mediated BBB modulation is known to activate microglia and astrocytes, which can exacerbate pathology or promote neuroprotection. I hypothesized that FUS induced a transient activation of microglia and astrocyte that is consistent with pro-regenerative functions. Firstly, I developed a method, MORPHological assessment of Outlier clusters (MORPHIOUS), to quantify microglial and astrocytic activation. MORPHIOUS is a machine learning tool that detects clusters of activated glia in histological sections by referencing control sample cell morphologies. As validation, identified clusters of activated microglia and astrocytes exhibited hallmark morphological and marker changes. Indeed, activated microglia were deramified and upregulated transforming growth factor beta 1 (Tgfβ1), and activated astrocytes were hypertrophic and expressed nestin. MORPHIOUS can therefore sensitively detect activated glia. Secondly, I used MORPHIOUS to characterize microglial and astrocytic activation from 1 to 30 days (D) post-FUS. Microglial activation peaked at 1D and was progressively attenuated between 4D and 30D post-FUS. Activated microglia predominantly colocalized with Tgfβ1, indicative of anti-inflammatory and neuroprotective functions; but not with the inflammation-associated cluster of differentiation 68. Astrocytic activation peaked at 4D and was significantly attenuated by 30D post-FUS. Activated astrocytes did not significantly proliferate or upregulate glial scar components. Thus, post-FUS glial activation was transient, and not indicative of pathology. Thirdly, to evaluate the regenerative potential of the brain environment post-FUS, I characterized neural progenitor cell (NPC) proliferation and oligodendrogenesis. NPC proliferation increased between 4D and 7D post-FUS and coincided with the activated astrocytic upregulation of insulin-like growth factor 2. Moreover, an increased proliferation of oligodendrocyte progenitors increased between 1D and 4D, promoted the number of newly developed oligodendrocytes at 30D. Therefore, post-FUS glial activation is permissive of broader brain regenerative programs. Collectively, this data supports my hypothesis by demonstrating that the FUS-mediated activation of microglia and astrocytes is transient, upregulates regenerative factors, and occurs alongside enhanced neurogenesis and oligodendrogenesis. This work positions FUS-mediated BBB permeabilization as a promising component of multimodal therapies, with potential to aid in the treatment of neurodegenerative disorders.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,031 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,002 | 0,001 |
| 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) | 0,000 | 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 tête enseignante, 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 ».