Background—Human cardiac progenitor cells (hCPCs) may promote myocardial regenerationin adult ischemic myocardium. The regenerative capacity of hCPCs in young patients withnonischemic congenital heart defects for potential use in congenital heart defect repair warrantsexploration.

Methods and Results—Human right atrial specimens were obtained during routine congenitalcardiac surgery across 3 groups: neonates (age, <30 days), infants (age, 1 month to 2 years), andchildren (age, >2 to 13 years). C-kit+ hCPCs were 3-fold higher in neonates than in children >2years of age. hCPC proliferation was greatest during the neonatal period as evidenced by c-kit+Ki67+ expression but decreased with age. hCPC differentiation capacity was also greatest inneonatal right atrium as evidenced by c-kit+, NKX2–5+, NOTCH1+, and NUMB+ expression.Despite the age-dependent decline in resident hCPCs, we isolated and expanded right atrium–derived CPCs from all patients (n = 103) across all ages and diagnoses using the cardiospheremethod. Intact cardiospheres contained a mix of heart-derived cell subpopulations that includedcardiac progenitor cells expressing c-kit+, Islet-1, and supporting cells. The number of c-kit+expressing cells was highest in human cardiosphere-derived cells (hCDCs) grown from neonataland infant right atrium. Furthermore, hCDCs could differentiate into diverse cardiovascularlineages by in vitro differentiation assays. Transplanted hCDCs promoted greater myocardialregeneration and functional improvement in infarcted myocardium than transplanted cardiacfibroblasts.

Conclusions—Resident hCPCs are most abundant in the neonatal period and rapidly decreaseover time. hCDCs can be reproducibly isolated and expanded from young human myocardial

Rachana Mishra, PhD*, Kalpana Vijayan, PhD*, Evan J. Colletti, PhD, Daniel A. Harrington,PhD, Thomas S. Matthiesen, BS, David Simpson, PhD, Saik Kia Goh, BS, Brandon L.Walker, MS, Graça Almeida-Porada, MD, PhD, Deli Wang, MD, PhD, Carl L. Backer, MD,Samuel C. Dudley Jr, MD, Loren E. Wold, PhD, and Sunjay Kaushal, MD, PhDDivision of Cardiovascular-Thoracic Surgery, Children’s Memorial Hospital, Chicago, IL (R.M.,K.V., D.A.H., T.S.M., D.S., S.K.G., B.L.W., D.W., C.L.B., S.K.); Northwestern University FeinbergSchool of Medicine, Chicago, IL (C.L.B., S.K.); Department of Animal Biotechnology, University ofNevada, Reno (E.J.C., G.A.-P), Division of Cardiology, Department of Medicine, University ofIllinois at Chicago, Chicago (S.C.D.); and Center for Cardiovascular and Pulmonary Research,The Research Institute at Nationwide Children’s Hospital, The Ohio State University, Columbus,OH (L.E.W.)