Hahn Tissue Lab, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA.
J Alzheimers Dis. 2021;84(2):647-658. doi: 10.3233/JAD-215007.
A significant subset of patients with Alzheimer's disease (AD) exhibit low bone mineral density and are therefore more fracture-prone, relative to their similarly aged neurotypical counterparts. In addition to chronic immune hyperactivity, behavioral dysregulation of effector peripheral sympathetic neurons-which densely innervate bone and potently modulate bone remodeling-is implicated in this pathological bone reformation.
Thus, there exists a pressing need for a robust in vitro model which allows interrogation of the paracrine interactions between the putative mediators of AD-related osteopenia: sympathetic neurons (SNs) and mesenchymal stem cells (MSCs).
Toward this end, activated SN-like PC12 cells and bone marrow derived MSCs were cultured in poly(ethylene glycol) diacrylate (PEGDA) hydrogels in the presence or absence of the AD-relevant inflammatory cytokine tumor necrosis factor alpha (TNF-α) under mono- and co-culture conditions.
PC12s and MSCs exposed separately to TNF-α displayed increased expression of pro-inflammatory mediators and decreased osteopontin (OPN), respectively. These data indicate that TNF-α was capable of inducing a dysregulated state in both cell types consistent with AD. Co-culture of TNF-α-activated PC12s and MSCs further exacerbated pathological behaviors in both cell types. Specifically, PC12s displayed increased secretion of interleukin 6 relative to TNF-α stimulated monoculture controls. Similarly, MSCs demonstrated a further reduction in osteogenic capacity relative to TNF-α stimulated monoculture controls, as illustrated by a significant decrease in OPN and collagen type I alpha I chain.
Taken together, these data may indicate that dysregulated sympathetic activity may contribute to AD-related bone loss.
与年龄相仿的神经典型对照组相比，阿尔茨海默病（AD）患者中有相当一部分存在骨密度低，因此更容易骨折。除了慢性免疫过度活跃外，效应外周交感神经元的行为失调——这些神经元密集地支配着骨骼并强烈调节着骨骼重塑——也与这种病理性骨改建有关。
因此，迫切需要一种强大的体外模型，以研究AD 相关骨质疏松症的潜在介质：交感神经元（SNs）和间充质干细胞（MSCs）之间的旁分泌相互作用。
为此，在存在或不存在 AD 相关炎症细胞因子肿瘤坏死因子α（TNF-α）的情况下，将激活的类似于 SN 的 PC12 细胞和骨髓来源的 MSC 培养在聚乙二醇二丙烯酸酯（PEGDA）水凝胶中，在单核和共培养条件下。
分别暴露于 TNF-α的 PC12s 和 MSCs 显示促炎介质表达增加，骨桥蛋白（OPN）分别减少。这些数据表明，TNF-α能够诱导两种细胞类型的失调状态，与 AD 一致。TNF-α 激活的 PC12s 和 MSCs 的共培养进一步加剧了两种细胞类型的病理行为。具体而言，与 TNF-α刺激的单核培养对照相比，PC12s 显示出白细胞介素 6 的分泌增加。同样，与 TNF-α刺激的单核培养对照相比，MSCs 表现出进一步降低的成骨能力，如图所示，骨桥蛋白和 I 型胶原 α I 链显著减少。
综上所述，这些数据可能表明，失调的交感神经活动可能导致 AD 相关的骨丢失。
