Departments of Bioengineering and Materials Science and Engineering, University of California, Berkeley, CA, United States of America.
Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Galway, Ireland.
PLoS One. 2018 Mar 22;13(3):e0194679. doi: 10.1371/journal.pone.0194679. eCollection 2018.
Cell-based strategies for the treatment of ischemic diseases are at the forefront of tissue engineering and regenerative medicine. Cell therapies purportedly can play a key role in the neovascularization of ischemic tissue; however, low survival and poor cell engraftment with the host vasculature following implantation limits their potential to treat ischemic diseases. To overcome these limitations, we previously developed a growth factor sequestering hyaluronic acid (HyA)-based hydrogel that enhanced transplanted mouse cardiosphere-derived cell survival and formation of vasculature that anastomosed with host vessels. In this work, we examined the mechanism by which HyA hydrogels presenting transforming growth factor beta-1 (TGF-β1) promoted proliferation of more clinically relevant human cardiosphere-derived cells (hCDC), and their formation of vascular-like networks in vitro. We observed hCDC proliferation and enhanced formation of vascular-like networks occurred in the presence of TGF-β1. Furthermore, production of nitric oxide (NO), VEGF, and a host of angiogenic factors were increased in the presence of TGF-β1. This response was dependent on the co-activity of CD105 (Endoglin) with the TGF-βR2 receptor, demonstrating its role in the process of angiogenic differentiation and vascular organization of hCDC. These results demonstrated that hCDC form vascular-like networks in vitro, and that the induction of vascular networks by hCDC within growth factor sequestering HyA hydrogels was mediated by TGF-β1/CD105 signaling.
基于细胞的治疗策略是组织工程和再生医学的前沿。细胞疗法据称可以在缺血组织的血管新生中发挥关键作用；然而，移植后细胞的存活率低且与宿主血管的植入不良限制了它们治疗缺血性疾病的潜力。为了克服这些限制，我们之前开发了一种生长因子隔离透明质酸（HyA）基水凝胶，该水凝胶增强了移植的小鼠心脏球源性细胞的存活和与宿主血管吻合的血管形成。在这项工作中，我们研究了 HyA 水凝胶呈现转化生长因子β-1（TGF-β1）促进更具临床相关性的人心球源性细胞（hCDC）增殖及其在体外形成血管样网络的机制。我们观察到 TGF-β1 的存在促进了 hCDC 的增殖和血管样网络的形成。此外，在 TGF-β1 的存在下，NO、VEGF 和一系列血管生成因子的产生增加。这种反应依赖于 CD105（Endoglin）与 TGF-βR2 受体的共同活性，表明其在 hCDC 的血管生成分化和血管组织中的作用。这些结果表明 hCDC 在体外形成血管样网络，并且 hCDC 在生长因子隔离 HyA 水凝胶内形成血管网络是由 TGF-β1/CD105 信号介导的。
