Lee Sue Hyun, Lee Yunki, Chun Young Wook, Crowder Spencer W, Young Pampee P, Park Ki Dong, Sung Hak-Joon
Dept. of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235 USA; Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN, 37235 USA.
Dept. of Molecular Science & Technology, Ajou University, Suwon 443-749 South Korea.
Adv Funct Mater. 2014 Nov 19;24(43):6771-6781. doi: 10.1002/adfm.201401110.
Clinical trials utilizing mesenchymal stem cells (MSCs) for severe vascular diseases have highlighted the need to effectively engraft cells and promote pro-angiogenic activity. A functional material accomplishing these two goals is an ideal solution as spatiotemporal and batch-to-batch variability in classical therapeutic delivery can be minimized, and tissue regeneration would begin rapidly at the implantation site. Gelatin may serve as a promising biomaterial due to its excellent biocompatibility, biodegradability, and non-immuno/antigenicity. However, the dissolution of gelatin at body temperature and quick enzymatic degradation o have limited its use thus far. To overcome these challenges, an injectable, crosslinkable gelatin was developed by conjugating enzymatically-crosslinkable hydroxyphenyl propionic acid (GHPA). When MSCs are cultured in 3D or injected in GHPA, spontaneous endothelial differentiation occurs, as evidenced by marked increases in endothlelial cell marker expressions () in addition to forming an extensive perfusable vascular network after 2-week subcutaneous implantation. Additionally, favorable host macrophage response is achieved with GHPA as shown by decreased iNOS and increased MRC1 expression. These results indicate GHPA as a promising soluble factor-free cell delivery template which induces endothelial differentiation of MSCs with robust neovasculature formation and favorable host response.
利用间充质干细胞（MSCs）治疗严重血管疾病的临床试验凸显了有效植入细胞并促进促血管生成活性的必要性。一种能够实现这两个目标的功能性材料是理想的解决方案，因为传统治疗递送中的时空和批次间变异性可以最小化，并且组织再生将在植入部位迅速开始。由于明胶具有出色的生物相容性、生物降解性和非免疫/抗原性，它可能是一种有前途的生物材料。然而，明胶在体温下的溶解和快速的酶促降解迄今为止限制了其应用。为了克服这些挑战，通过共轭可酶促交联的羟苯基丙酸（GHPA）开发了一种可注射的、可交联的明胶。当MSCs在3D中培养或注射到GHPA中时，会发生自发的内皮分化，除了在皮下植入2周后形成广泛的可灌注血管网络外，内皮细胞标志物表达（）也显著增加，这证明了这一点。此外，GHPA还实现了良好的宿主巨噬细胞反应，iNOS表达降低和MRC1表达增加表明了这一点。这些结果表明，GHPA是一种有前途的无可溶性因子的细胞递送模板，可诱导MSCs的内皮分化，并形成强大的新血管生成和良好的宿主反应。
