Lee Yunki, Balikov Daniel A, Lee Jung Bok, Lee Sue Hyun, Lee Seung Hwan, Lee Jong Hun, Park Ki Dong, Sung Hak-Joon
Department of Biomedical Engineering, Vanderbilt University, Nasville, TN 37235, USA.
Severance Biomedical Science Institute, College of Medicine, Yonsei University, Seoul 120-752, Korea.
Int J Mol Sci. 2017 Aug 4;18(8):1705. doi: 10.3390/ijms18081705.
Directing angiogenic differentiation of mesenchymal stem cells (MSCs) still remains challenging for successful tissue engineering. Without blood vessel formation, stem cell-based approaches are unable to fully regenerate damaged tissues due to limited support for cell viability and desired tissue/organ functionality. Herein, we report in situ cross-linkable gelatin-hydroxyphenyl propionic acid (GH) hydrogels that can induce pro-angiogenic profiles of MSCs via purely material-driven effects. This hydrogel directed endothelial differentiation of mouse and human patient-derived MSCs through integrin-mediated interactions at the cell-material interface, thereby promoting perfusable blood vessel formation in vitro and in vivo. The causative roles of specific integrin types (α₁ and αβ₃) in directing endothelial differentiation were verified by blocking the integrin functions with chemical inhibitors. In addition, to verify the material-driven effect is not species-specific, we confirmed in vitro endothelial differentiation and in vivo blood vessel formation of patient-derived human MSCs by this hydrogel. These findings provide new insight into how purely material-driven effects can direct endothelial differentiation of MSCs, thereby promoting vascularization of scaffolds towards tissue engineering and regenerative medicine applications in humans.
引导间充质干细胞（MSCs）的血管生成分化对于成功的组织工程来说仍然具有挑战性。如果没有血管形成，基于干细胞的方法就无法完全再生受损组织，因为对细胞活力和所需组织/器官功能的支持有限。在此，我们报告了原位可交联的明胶-羟基苯丙酸（GH）水凝胶，其可通过纯粹的材料驱动效应诱导MSCs的促血管生成特性。这种水凝胶通过细胞-材料界面处整合素介导的相互作用引导小鼠和人类患者来源的MSCs向内皮细胞分化，从而在体外和体内促进可灌注血管的形成。通过用化学抑制剂阻断整合素功能，验证了特定整合素类型（α₁和αβ₃）在引导内皮细胞分化中的因果作用。此外，为了验证材料驱动效应不是物种特异性的，我们证实了这种水凝胶可使患者来源的人类MSCs在体外向内皮细胞分化并在体内形成血管。这些发现为纯粹的材料驱动效应如何引导MSCs向内皮细胞分化提供了新的见解，从而促进支架血管化以用于人类的组织工程和再生医学应用。
