Stem cell-based microphysiological osteochondral system to model tissue response to interleukin-1β.
Stem cell-based microphysiological osteochondral system to model tissue response to interleukin-1β.
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DOI：
10.1021/mp500136b
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发表时间：
2014-07-07
影响因子：
4.9
通讯作者：
Tuan RS
中科院分区：
文献类型：
--
作者：
Lin H;Lozito TP;Alexander PG;Gottardi R;Tuan RS
骨关节炎（OA）是一种关节慢性退行性疾病，涉及骨和软骨退行性变化。生理条件下的工程化骨软骨组织对于了解 OA 的发病机制和测试潜在的缓解 OA 疾病药物 (DMOAD) 的功效具有重要意义。在这项研究中，制造了一个多室生物反应器并将其安装到微流体底座中。当插入骨软骨结构时，结构的两侧形成两个腔室（顶部，软骨；底部，骨），由不同的介质流提供。这些介质导管对于创建软骨和骨组织发育和成熟的组织特异性微环境至关重要。原位制造人骨髓干细胞 (hBMSC) 衍生的构建体并在生物反应器内培养，并在组织特异性培养基中诱导进行空间限定的软骨形成和成骨分化 4 周。我们观察到组织特异性基因表达和基质产生以及嗜碱性界面，表明正在发展的潮汐标记。将白细胞介素-1β (IL-1β) 引入软骨或骨介质流中，会在局部以及相反的组织类型中诱导更强的降解反应。例如，骨室的 IL-1β 处理导致软骨层产生强烈的分解代谢反应，基质金属蛋白酶 (MMP) 表达和活性以及组织特异性基因表达增加表明。这种诱导作用强于直接将 IL-1β 应用于软骨成分所观察到的诱导作用，表明两个组织层之间存在活跃的生化通讯，并支持 OA 的骨软骨性质。这里开发的微组织培养系统为研究骨软骨组织的生理学和 OA 的致病机制提供了新的能力，并作为测试潜在 DMOADS 的高通量平台。
Osteoarthritis (OA) is a chronic degenerative disease of the articular joint that involves both bone and cartilage degenerative changes. An engineered osteochondral tissue within physiological conditions will be of significant utility in understanding the pathogenesis of OA and testing the efficacy of potential disease-modifying OA drugs (DMOADs). In this study, a multichamber bioreactor was fabricated and fitted into a microfluidic base. When the osteochondral construct is inserted, two chambers are formed on either side of the construct (top, chondral; bottom, osseous) that is supplied by different medium streams. These medium conduits are critical to create tissue-specific microenvironments in which chondral and osseous tissues will develop and mature. Human bone marrow stem cell (hBMSCs)-derived constructs were fabricated in situ and cultured within the bioreactor and induced to undergo spatially defined chondrogenic and osteogenic differentiation for 4 weeks in tissue-specific media. We observed tissue specific gene expression and matrix production as well as a basophilic interface suggesting a developing tidemark. Introduction of interleukin-1β (IL-1β) to either the chondral or osseous medium stream induced stronger degradative responses locally as well as in the opposing tissue type. For example, IL-1β treatment of the osseous compartment resulted in a strong catabolic response in the chondral layer as indicated by increased matrix metalloproteinase (MMP) expression and activity, and tissue-specific gene expression. This induction was greater than that seen with IL-1β application to the chondral component directly, indicative of active biochemical communication between the two tissue layers and supporting the osteochondral nature of OA. The microtissue culture system developed here offers novel capabilities for investigating the physiology of osteochondral tissue and pathogenic mechanisms of OA and serving as a high-throughput platform to test potential DMOADS.
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