Osteoinductivity of engineered cartilaginous templates devitalized by inducible apoptosis
Osteoinductivity of engineered cartilaginous templates devitalized by inducible apoptosis
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DOI：
10.1073/pnas.1411975111
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发表时间：
2014-12-09
影响因子：
11.1
通讯作者：
Martin, Ivan
中科院分区：
文献类型：
--
作者：
Bourgine, Paul E.;Scotti, Celeste;Martin, Ivan
无细胞的细胞外基质（ECM）在触发组织和器官再生中的作用已经获得了越来越多的认识，然而目前的方法主要基于在非同源位点使用来自完全发育的天然组织的ECM。我们描述了一种策略，以产生定制的ECM，旨在激活内源性再生程序重演组织特异性的发展过程。通过测试工程化和失活的肥大软骨的骨诱导能力，在骨骼系统的背景下举例说明了该范例，肥大软骨是大多数骨骼发育的原始模板。ECM是通过诱导人间充质基质细胞的软骨形成而工程化的，并通过实施死亡诱导型遗传装置而失活，从而导致活化和基质蛋白保存的细胞凋亡。在严格的异位植入模型中测试的所得肥大软骨ECM有效地重塑以形成宿主来源的从头骨组织，包括成熟的脉管系统和造血隔室。重要的是，如果通过标准的“冻融”（F&T）循环失活，软骨ECM不能产生坦率的骨组织，这与糖胺聚糖、矿物质含量和ECM结合的细胞因子的显著损失相关，所述细胞因子与炎症、血管化和重塑过程密切相关。这些结果支持工程化的基于ECM的装置作为现成的再生小生境的效用，所述再生小生境能够募集和指导驻留细胞朝向特定组织的形成。
The role of cell-free extracellular matrix (ECM) in triggering tissue and organ regeneration has gained increased recognition, yet current approaches are predominantly based on the use of ECM from fully developed native tissues at nonhomologous sites. We describe a strategy to generate customized ECM, designed to activate endogenous regenerative programs by recapitulating tissue-specific developmental processes. The paradigm was exemplified in the context of the skeletal system by testing the osteoinductive capacity of engineered and devitalized hypertrophic cartilage, which is the primordial template for the development of most bones. ECM was engineered by inducing chondrogenesis of human mesenchymal stromal cells and devitalized by the implementation of a death-inducible genetic device, leading to cell apoptosis on activation and matrix protein preservation. The resulting hypertrophic cartilage ECM, tested in a stringent ectopic implantation model, efficiently remodeled to form de novo bone tissue of host origin, including mature vasculature and a hematopoietic compartment. Importantly, cartilage ECM could not generate frank bone tissue if devitalized by standard "freeze & thaw" (F&T) cycles, associated with a significant loss of glycosaminoglycans, mineral content, and ECM-bound cytokines critically involved in inflammatory, vascularization, and remodeling processes. These results support the utility of engineered ECM-based devices as off-the-shelf regenerative niches capable of recruiting and instructing resident cells toward the formation of a specific tissue.