title: The modulation of cardiac progenitor cell function by hydrogel-dependent Notch1 activation.
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.
authors: 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.
authors: Archana V
authors: AV
authors: Boopathy
authors: Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA.
authors: Pao Lin
authors: PL
authors: Che
authors: 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.
authors: Inthirai
authors: I
authors: Somasuntharam
authors: Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors: Vincent F
authors: VF
authors: Fiore
authors: Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA.
authors: E Bernadette
authors: EB
authors: Cabigas
authors: Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Kiwon
authors: K
authors: Ban
authors: Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA; Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Milton E
authors: ME
authors: Brown
authors: Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
authors: Yoshie
authors: Y
authors: Narui
authors: Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors: Thomas H
authors: TH
authors: Barker
authors: Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Young-Sup
authors: YS
authors: Yoon
authors: Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
authors: Khalid
authors: K
authors: Salaita
authors: 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; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors: Andrés J
authors: AJ
authors: García
authors: 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; Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA; Emory+Children's Center for Cardiovascular Biology, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA. Electronic address: michael.davis@bme.emory.edu.
authors: Michael E
authors: ME
authors: Davis
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D016466:CHO Cells; D002454:Cell Differentiation; D002465:Cell Movement; D004396:Coloring Agents / Q000737:chemistry; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020100:Hydrogels / Q000737:chemistry*; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology; D010455:Peptides / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D001672:Biocompatible Materials; D004396:Coloring Agents; D020100:Hydrogels; C497762:Notch1 protein, mouse; C497763:Notch1 protein, rat; D010455:Peptides; D011108:Polymers; D051881:Receptor, Notch1
keywords: Gene expression; Heart; Hydrogel; Progenitor cell; Self assembling peptide