(422f) Modeling Sympathetic Hyperactivity in Alzheimer’s Related Bone Resorption
AIChE Annual Meeting
2021
2021 Annual Meeting
Food, Pharmaceutical & Bioengineering Division
Engineering in Aging and Aging-Associated Diseases
Wednesday, November 10, 2021 - 9:30am to 9:48am
A significant subset of Alzheimerâs Disease (AD) patients exhibit low bone mineral density and are therefore more fracture-prone relative to similarly aged neurotypical populations. In addition to chronic immune hyperactivity, behavioral dysregulation of effector peripheral sympathetic neurons (SNs) â which densely innervate bone tissue and potently regulate bone remodeling â has been implicated in this pathology. The current clinical âgold standardâ for stimulating functional regeneration of damaged bone tissue involves the implementation of harvested autografts; however, positive outcomes are limited due to finite donor availability, donor site morbidity, complex grafting procedures, and high engraftment failure rates. Thus, there exists a pressing need for a robust in vitro model which can be applied toward generating novel tissue engineering treatment strategies â one which faithfully recapitulates the paracrine interactions observed between the predominant mediators of Alzheimerâs related osteopenia: SNs and mesenchymal stem cells (MSCs). Toward this end, we cocultured activated SN-like PC12s and human MSCs (hMSCs) in a poly(ethylene glycol) diacrylate (PEGDA) transwell architecture.The presence of SN-like PC12s and inflammatory culture conditions exerted differential effects on the osteo-regulatory profile of hMSCs. TNF- induced a significant decrease in angiogenic factor VEGF, and osteogenic factor BMP-2, in hMSCs irrespective of coculture with PC12s; however, the effects of PC12 coculture dominated in generating a decrease in COL1A1, the predominant structural protein in bone. Furthermore, the combined effects of PC12 coculture and TNF- stimulation engendered a nearly 10-fold reduction in OPN, a regulator of bone mineralization. These results support the hypothesis that activated SN-like PC12 cells indeed potently inhibit the osteogenesis of hMSCs.
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