Characterization and functionality of cardiac progenitor cells in congenital heart patients.
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.


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.
Children's Memorial Hospital, Division of Cardiovascular-Thoracic Surgery, 2300 Children's Plaza, Chicago, IL 60614, USA.
Rachana
R
Mishra
Kalpana
K
Vijayan
Evan J
EJ
Colletti
Daniel A
DA
Harrington
Thomas S
TS
Matthiesen
David
D
Simpson
Saik Kia
SK
Goh
Brandon L
BL
Walker
Graça
G
Almeida-Porada
Deli
D
Wang
Carl L
CL
Backer
Samuel C
SC
Dudley
Loren E
LE
Wold
Sunjay
S
Kaushal
D000293:Adolescent; D000367:Age Factors; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D006330:Heart Defects, Congenital / Q000601:surgery*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000502:physiology* / Q000637:transplantation*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D051881:Receptor, Notch1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D008565:Membrane Proteins; C095552:NKX2-5 protein, human; C497761:NOTCH1 protein, human; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D051881:Receptor, Notch1; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit
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