Boopathy Archana V, Che Pao Lin, Somasuntharam Inthirai, Fiore Vincent F, Cabigas E Bernadette, Ban Kiwon, Brown Milton E, Narui Yoshie, Barker Thomas H, Yoon Young-Sup, Salaita Khalid, García Andrés J, Davis Michael E
Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA; Interdisciplinary BioEngineering Program, Georgia Institute of Technology, Atlanta, GA 30332, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA.
Biomaterials. 2014 Sep;35(28):8103-12. doi: 10.1016/j.biomaterials.2014.05.082. Epub 2014 Jun 25.
Myocardial infarction is the leading cause of death worldwide and phase I clinical trials utilizing cardiac progenitor cells (CPCs) have shown promising outcomes. Notch1 signaling plays a critical role in cardiac development and in the survival, cardiogenic lineage commitment, and differentiation of cardiac stem/progenitor cells. In this study, we functionalized self-assembling peptide (SAP) hydrogels with a peptide mimic of the Notch1 ligand Jagged1 (RJ) to evaluate the therapeutic benefit of CPC delivery in the hydrogels in a rat model of myocardial infarction. The behavior of CPCs cultured in the 3D hydrogels in vitro including gene expression, proliferation, and growth factor production was evaluated. Interestingly, we observed Notch1 activation to be dependent on hydrogel polymer density/stiffness with synergistic increase in presence of RJ. Our results show that RJ mediated Notch1 activation depending on hydrogel concentration differentially regulated cardiogenic gene expression, proliferation, and growth factor production in CPCs in vitro. In rats subjected to experimental myocardial infarction, improvement in acute retention and cardiac function was observed following cell therapy in RJ hydrogels compared to unmodified or scrambled peptide containing hydrogels. This study demonstrates the potential therapeutic benefit of functionalizing SAP hydrogels with RJ for CPC based cardiac repair.
心肌梗死是全球范围内主要的死亡原因，利用心脏祖细胞（CPCs）进行的I期临床试验已显示出有前景的结果。Notch1信号通路在心脏发育以及心脏干/祖细胞的存活、向心脏谱系的定向分化和分化过程中起着关键作用。在本研究中，我们用Notch1配体Jagged1（RJ）的肽模拟物对自组装肽（SAP）水凝胶进行功能化，以评估在大鼠心肌梗死模型中，水凝胶中递送CPCs的治疗益处。评估了CPCs在3D水凝胶中体外培养时的行为，包括基因表达、增殖和生长因子产生。有趣的是，我们观察到Notch1激活取决于水凝胶聚合物密度/硬度，在RJ存在时协同增加。我们的结果表明，RJ介导的Notch1激活取决于水凝胶浓度，在体外对CPCs中的心脏发生基因表达、增殖和生长因子产生有不同的调节作用。在实验性心肌梗死的大鼠中，与未修饰或含乱序肽的水凝胶相比，在RJ水凝胶中进行细胞治疗后，观察到急性滞留和心脏功能有所改善。本研究证明了用RJ对SAP水凝胶进行功能化用于基于CPCs的心脏修复的潜在治疗益处。
