Sudhish Sharma1, Rachana Mishra1, Grace E Bigham1, Brody Wehman1, Mohd M Khan1, Huichun Xu1, Progyaparamita Saha1, Young Ah Goo1, Srinivasa Raju Datla1, Ling Chen1, Mohan E Tulapurkar1, Bradley S Taylor1, Peixin Yang1, Sotirios Karathanasis1, David R Goodlett1, Sunjay Kaushal2. 1. From the Division of Cardiac Surgery, School of Medicine (S.S., R.M., G.E.B., B.W., P.S., S.R.D., B.S.T., S.K.), Department of Pharmaceutical Sciences, School of Pharmacy (M.M.K., Y.A.G., D.R.G.), Division of Endocrinology, Diabetes and Nutrition, Department of Medicine (H.X.), Department of Physiology and Medicine, School of Medicine (L.C.), Department of OB/GYN & Reproductive Science, Department of Biochemistry and Molecular Biology, School of Medicine (P.Y.), and Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine (M.E.T.), University of Maryland, Baltimore; and Cardiovascular and Metabolic Diseases, Innovative Medicines Biotech Unit MedImmune, Inc., Gaithersburg, MD (S.K.). 2. From the Division of Cardiac Surgery, School of Medicine (S.S., R.M., G.E.B., B.W., P.S., S.R.D., B.S.T., S.K.), Department of Pharmaceutical Sciences, School of Pharmacy (M.M.K., Y.A.G., D.R.G.), Division of Endocrinology, Diabetes and Nutrition, Department of Medicine (H.X.), Department of Physiology and Medicine, School of Medicine (L.C.), Department of OB/GYN & Reproductive Science, Department of Biochemistry and Molecular Biology, School of Medicine (P.Y.), and Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine (M.E.T.), University of Maryland, Baltimore; and Cardiovascular and Metabolic Diseases, Innovative Medicines Biotech Unit MedImmune, Inc., Gaithersburg, MD (S.K.). skaushal@smail.umaryland.edu.
Abstract
RATIONALE: Cardiac progenitor cells are an attractive cell type for tissue regeneration, but their mechanism for myocardial remodeling is still unclear. OBJECTIVE: This investigation determines how chronological age influences the phenotypic characteristics and the secretome of human cardiac progenitor cells (CPCs), and their potential to recover injured myocardium. METHODS AND RESULTS: Adult (aCPCs) and neonatal (nCPCs) cells were derived from patients aged >40 years or <1 month, respectively, and their functional potential was determined in a rodent myocardial infarction model. A more robust in vitro proliferative capacity of nCPCs, compared with aCPCs, correlated with significantly greater myocardial recovery mediated by nCPCs in vivo. Strikingly, a single injection of nCPC-derived total conditioned media was significantly more effective than nCPCs, aCPC-derived TCM, or nCPC-derived exosomes in recovering cardiac function, stimulating neovascularization, and promoting myocardial remodeling. High-resolution accurate mass spectrometry with reverse phase liquid chromatography fractionation and mass spectrometry was used to identify proteins in the secretome of aCPCs and nCPCs, and the literature-based networking software identified specific pathways affected by the secretome of CPCs in the setting of myocardial infarction. Examining the TCM, we quantified changes in the expression pattern of 804 proteins in nCPC-derived TCM and 513 proteins in aCPC-derived TCM. The literature-based proteomic network analysis identified that 46 and 6 canonical signaling pathways were significantly targeted by nCPC-derived TCM and aCPC-derived TCM, respectively. One leading candidate pathway is heat-shock factor-1, potentially affecting 8 identified pathways for nCPC-derived TCM but none for aCPC-derived TCM. To validate this prediction, we demonstrated that the modulation of heat-shock factor-1 by knockdown in nCPCs or overexpression in aCPCs significantly altered the quality of their secretome. CONCLUSIONS: A deep proteomic analysis revealed both detailed and global mechanisms underlying the chronological age-based differences in the ability of CPCs to promote myocardial recovery via the components of their secretome.
RATIONALE: Cardiac progenitor cells are an attractive cell type for tissue regeneration, but their mechanism for myocardial remodeling is still unclear. OBJECTIVE: This investigation determines how chronological age influences the phenotypic characteristics and the secretome of human cardiac progenitor cells (CPCs), and their potential to recover injured myocardium. METHODS AND RESULTS: Adult (aCPCs) and neonatal (nCPCs) cells were derived from patients aged >40 years or <1 month, respectively, and their functional potential was determined in a rodent myocardial infarction model. A more robust in vitro proliferative capacity of nCPCs, compared with aCPCs, correlated with significantly greater myocardial recovery mediated by nCPCs in vivo. Strikingly, a single injection of nCPC-derived total conditioned media was significantly more effective than nCPCs, aCPC-derived TCM, or nCPC-derived exosomes in recovering cardiac function, stimulating neovascularization, and promoting myocardial remodeling. High-resolution accurate mass spectrometry with reverse phase liquid chromatography fractionation and mass spectrometry was used to identify proteins in the secretome of aCPCs and nCPCs, and the literature-based networking software identified specific pathways affected by the secretome of CPCs in the setting of myocardial infarction. Examining the TCM, we quantified changes in the expression pattern of 804 proteins in nCPC-derived TCM and 513 proteins in aCPC-derived TCM. The literature-based proteomic network analysis identified that 46 and 6 canonical signaling pathways were significantly targeted by nCPC-derived TCM and aCPC-derived TCM, respectively. One leading candidate pathway is heat-shock factor-1, potentially affecting 8 identified pathways for nCPC-derived TCM but none for aCPC-derived TCM. To validate this prediction, we demonstrated that the modulation of heat-shock factor-1 by knockdown in nCPCs or overexpression in aCPCs significantly altered the quality of their secretome. CONCLUSIONS: A deep proteomic analysis revealed both detailed and global mechanisms underlying the chronological age-based differences in the ability of CPCs to promote myocardial recovery via the components of their secretome.
Authors: Georgina M Ellison; Daniele Torella; Santo Dellegrottaglie; Claudia Perez-Martinez; Armando Perez de Prado; Carla Vicinanza; Saranya Purushothaman; Valentina Galuppo; Claudio Iaconetti; Cheryl D Waring; Andrew Smith; Michele Torella; Carlos Cuellas Ramon; Jose Manuel Gonzalo-Orden; Valter Agosti; Ciro Indolfi; Manuel Galiñanes; Felipe Fernandez-Vazquez; Bernardo Nadal-Ginard Journal: J Am Coll Cardiol Date: 2011-06-30 Impact factor: 24.094
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