The modulation of cardiac progenitor cell function by hydrogel-dependent Notch1 activation

• Type of Material: Article
• Authors: Archana V. Boopathy, Emory University; Pao Lin Che, Emory University; Inthirai Somasuntharam, Emory University; Vincent F. Fiore, Emory University; E. Bernadette Cabigas, Emory University; Kiwon Ban, Emory University; Milton Brown, Emory University; Yoshie Narui, Emory University; Thomas Barker, Emory University; Young-sup Yoon, Emory University; Khalid Salaita, Emory University; Andres J. Garcia, Georgia Institute of Technology; Michael Davis, Emory University
• Language: English
• Date: 2014-09-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biomaterials.2014.05.082
• Title of Journal or Parent Work: Biomaterials
• ISSN: 0142-9612
• Volume: 35
• Issue: 28
• Start Page: 8103
• End Page: 8112
• Grant/Funding Information: This publication has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN268201000043C to MED.; This work was also supported by funding from the National Institutes of Health grant DP3DK094346 to YY; and an American Heart Association Predoctoral fellowship 11PRE7840078 to AVB.
• Keywords: SURVIVAL; Science & Technology; Materials Science, Biomaterials; DELIVERY; SIGNALING PROMOTES; PATHWAY; STEM-CELLS; Gene expression; Hydrogel; Technology; PDGF-BB; MIGRATION; Engineering, Biomedical; HEART REGENERATION; Materials Science; Heart; KAPPA-B; MATURATION; Engineering; Self assembling peptide; Progenitor cell
• Research Categories: Engineering, Biomedical; Chemistry, General; Health Sciences, Medicine and Surgery

Abstract

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.