Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis
Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis
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DOI：
10.1073/pnas.1214100110
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发表时间：
2013-06-18
影响因子：
11.1
通讯作者：
Burdick, Jason A.
中科院分区：
文献类型：
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作者：
Bian, Liming;Guvendiren, Murat;Burdick, Jason A.
甲基丙烯酸化透明质酸（HA）水凝胶提供了一种主链聚合物，间充质干细胞（MSCs）可通过其自身表达的几种细胞表面受体（包括CD44和CD168）与之相互作用。先前的研究表明，这种三维水凝胶环境支持间充质干细胞的软骨形成，在此我们通过功能性阻断证明这些特定的细胞 - 材料相互作用在此过程中起作用。除了基质相互作用外，钙黏蛋白分子（一种跨膜糖蛋白家族）在胚胎发生过程中的组织发育中起关键作用，并且N - 钙黏蛋白是在间充质凝聚和软骨形成过程中调节细胞 - 细胞相互作用的关键因素。在这项研究中，我们用N - 钙黏蛋白模拟肽对HA水凝胶进行功能化，并评估它们在调节包封的间充质干细胞的软骨形成和软骨基质沉积中的作用。我们的结果表明，与未修饰的对照组或包含无序肽结构域的对照组相比，将钙黏蛋白肽结合到HA水凝胶上可促进间充质干细胞的早期软骨形成以及随着培养过程中软骨特异性基质的产生。通过用N - 钙黏蛋白特异性抗体处理，这种增强的软骨形成作用被消除，证实了这些N - 钙黏蛋白肽对软骨形成的贡献。间充质干细胞接种构建体的皮下植入也表明，与对照组相比，用N - 钙黏蛋白模拟肽功能化的植入物中形成了更好的新软骨。这项研究证明了基于HA的水凝胶固有的生物活性，以及对HA水凝胶进行生物功能化以模拟胚胎发生过程中自然细胞微环境复杂性的前景，特别是在基于干细胞的软骨再生方面。
Methacrylated hyaluronic acid (HA) hydrogels provide a backbone polymer with which mesenchymal stem cells (MSCs) can interact through several cell surface receptors that are expressed by MSCs, including CD44 and CD168. Previous studies showed that this 3D hydrogel environment supports the chondrogenesis of MSCs, and here we demonstrate through functional blockade that these specific cell-material interactions play a role in this process. Beyond matrix interactions, cadherin molecules, a family of transmembrane glycoproteins, play a critical role in tissue development during embryogenesis, and N-cadherin is a key factor in mediating cell-cell interactions during mesenchymal condensation and chondrogenesis. In this study, we functionalized HA hydrogels with N-cadherin mimetic peptides and evaluated their role in regulating chondrogenesis and cartilage matrix deposition by encapsulated MSCs. Our results show that conjugation of cadherin peptides onto HA hydrogels promotes both early chondrogenesis of MSCs and cartilage-specific matrix production with culture, compared with unmodified controls or those with inclusion of a scrambled peptide domain. This enhanced chondrogenesis was abolished via treatment with N-cadherin-specific antibodies, confirming the contribution of these N-cadherin peptides to chondrogenesis. Subcutaneous implantation of MSC-seeded constructs also showed superior neocartilage formation in implants functionalized with N-cadherin mimetic peptides compared with controls. This study demonstrates the inherent biologic activity of HA-based hydrogels, as well as the promise of biofunctionalizing HA hydrogels to emulate the complexity of the natural cell microenvironment during embryogenesis, particularly in stem cell-based cartilage regeneration.