Journal
CIRCULATION
Volume 123, Issue 4, Pages 364-U276Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.110.971622
Keywords
heart defects, congenital; cardiomyopathy; heart failure; remodeling; pediatrics; stem cells
Funding
- National Institutes of Health [KO8HL097069]
- Thoracic Surgical Foundation for Research and Education
- Children's Heart Foundation
- North Suburban Medical Research Junior Board
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Background-Human cardiac progenitor cells (hCPCs) may promote myocardial regeneration in adult ischemic myocardium. The regenerative capacity of hCPCs in young patients with nonischemic congenital heart defects for potential use in congenital heart defect repair warrants exploration. Methods and Results-Human right atrial specimens were obtained during routine congenital cardiac surgery across 3 groups: neonates (age, < 30 days), infants (age, 1 month to 2 years), and children (age, > 2 to <= 13 years). C-kit(+) hCPCs were 3-fold higher in neonates than in children > 2 years 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 in neonatal 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 cardiosphere method. Intact cardiospheres contained a mix of heart-derived cell subpopulations that included cardiac 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 neonatal and infant right atrium. Furthermore, hCDCs could differentiate into diverse cardiovascular lineages by in vitro differentiation assays. Transplanted hCDCs promoted greater myocardial regeneration and functional improvement in infarcted myocardium than transplanted cardiac fibroblasts. Conclusions-Resident hCPCs are most abundant in the neonatal period and rapidly decrease over time. hCDCs can be reproducibly isolated and expanded from young human myocardial samples regardless of age or diagnosis. hCPCs are functional and have potential in congenital cardiac repair. (Circulation. 2011;123:364-373.)
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