Pediatric End-Stage Failing Hearts Demonstrate Increased Cardiac Stem Cells Brody Wehman, MD, Sudhish Sharma, PhD, Rachana Mishra, PhD, Yin Guo, PhD,

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Pediatric End-Stage Failing Hearts Demonstrate Increased Cardiac Stem Cells Brody Wehman, MD, Sudhish Sharma, PhD, Rachana Mishra, PhD, Yin Guo, PhD, Evan J. Colletti, PhD, Zachary N. Kon, MD, Srinivasa Raju Datla, PhD, Osama T. Siddiqui, MD, Keerti Balachandran, MS, Sunjay Kaushal, MD, PhD The Annals of Thoracic Surgery Volume 100, Issue 2, Pages 615-622 (August 2015) DOI: 10.1016/j.athoracsur.2015.04.088 Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 End-stage heart failure (ESHF) myocardium switches back to a fetal gene program and increases expression of endogenous c-kit+ cells. Quantitative real-time polymerase chain reaction from ESHF myocardium demonstrated decreased expression of (A) α-myosin heavy chain (α-MHC), increased expression of (B) β-myosin heavy chain (β-MHC), and (C) atrial natriuretic factor (ANF) compared with CHD myocardium. Quantitative real-time polymerase chain reaction for (D) c-kit suggests a 2-fold increase in the right atrium of ESHF as compared with CHD, and (E) a 2.5-fold increase of islet-1 (ISL-1) mRNA expression. (F) Confocal microscopy image showing c-kit+ cells (white arrow) from a patient with normal myocardium (magnification, ×40). (G) C-kit expression in myocardium from ESHF patients is age-independent and shows high expression with increasing age, in contrast to normal myocardium from CHD patients. *p < 0.05. The Annals of Thoracic Surgery 2015 100, 615-622DOI: (10.1016/j.athoracsur.2015.04.088) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 Expression profile of cardiac progenitor markers from explanted end-stage heart failure (ESHF) hearts. (A) Confocal microscopy image of islet-1 (ISL-1) cells within ESHF myocardium (magnification, ×40). Analysis of cardiac chambers from explanted ESHF revealed (B) a fourfold increase in ISL-1 mRNA levels in the right atrial appendage (RAA) compared with the left ventricle (LV) as determined by quantitative real-time polymerase chain reaction, and (C) increased expression of ISL-1 in right-side heart chambers relative to left. (D) Increased expression of c-kit in the right atrial appendage relative to other structures in ESHF hearts. (E) Representative images of RV myocardium from ESHF hearts showing coexpression of ISL-1 with the cardiac lineage marker GATA-4 was only present in 0.002% of ISL-1+ cells. *p < 0.05. (LAA = left atrial appendage.) The Annals of Thoracic Surgery 2015 100, 615-622DOI: (10.1016/j.athoracsur.2015.04.088) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 Surface marker expression of end-stage heart failure (ESHF) and congenital heart disease (CHD) -derived cardiac stem cells. (A) Representative dot plot of fluorescence-activated cell sorting analysis of antigenic phenotype of ESHF- and CHD-derived cardiac stem cells. (B) Expression of the stem cell marker c-kit expression was not found to be different in either population. Both kinds of cardiac stem cells were found to have similar expression of endothelial (CD31), hematopoietic (CD34, CD45), and mesenchymal (CD90, CD105) markers. The Annals of Thoracic Surgery 2015 100, 615-622DOI: (10.1016/j.athoracsur.2015.04.088) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 Growth properties of end-stage heart failure (ESHF) versus congenital heart disease (CHD)-derived c-kit+ cardiac stem cells and in vivo paracrine factor expression. (A) Comparison of telomere length in c-kit+ cardiac stem cells isolated from CHD versus ESHF myocardium. (B) Representative phase-contrast microscopy image of c-kit+ cardiac stem cell morphology with quantification of population doubling time. (C–K) In vivo comparison of growth factors (CHD, n = 5 versus ESHF, n = 5 for each): (C) angiopoietin 2 (Ang-2), (D) stromal-derived factor 1 (SDF-1), (E) vascular endothelial growth factor (VEGF), (F) fibroblast growth factor (FGF), (G) interleukin 8 (IL-8), (H) insulin growth factor 1 (IGF-1), (I) oxidative stress-induced growth inhibitor 1 (OSIGIN), (J) hypoxia-inducible factor 1 (HIF-1α), and (K) platelet-derived growth factor (PDGF-β). **p < 0.01. The Annals of Thoracic Surgery 2015 100, 615-622DOI: (10.1016/j.athoracsur.2015.04.088) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions