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Published on: January 7, 2019
Age-Dependent Effect of Pediatric Cardiac Progenitor Cells After Juvenile Heart Failure
Udit Agarwal1, Amanda W Smith1, Kristin M French1
1Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia, USA.
Insights
Neonatal human cardiac progenitor cells (hCPCs) significantly improved heart function in juvenile heart failure models. Cell age is crucial for effective stem cell therapy in pediatric heart repair, with younger cells showing greater benefits.
Area of Science:
- Regenerative Medicine
- Cardiovascular Research
- Pediatric Cardiology
Background:
- Congenital heart diseases (CHDs) lead to significant morbidity and mortality in children, necessitating improved therapeutic strategies.
- Current treatments for pediatric heart failure have limitations, highlighting the need for novel approaches like stem cell therapy.
- Understanding the factors influencing the efficacy of stem cell therapy in pediatric populations is critical for clinical translation.
Purpose of the Study:
- To investigate the impact of human cardiac progenitor cell (hCPC) age on ventricular remodeling in a juvenile right ventricular (RV) heart failure model.
- To compare the reparative potential of hCPCs from neonates, infants, and children in a rat model of pediatric heart failure.
- To elucidate the underlying mechanisms, including cellular function and gene-level changes, responsible for age-dependent therapeutic effects.
Main Methods:
- Isolation and age-based grouping (neonate, infant, child) of human cardiac progenitor cells (hCPCs).
- Establishment of a juvenile rat model of right ventricular (RV) heart failure via pulmonary artery banding.
- Noninvasive transplantation of hCPCs into the RV, followed by cardiac function analysis, computational modeling, and mechanistic assays.
Main Results:
- Transplantation of neonatal hCPCs significantly improved RV function, evidenced by increased tricuspid annular plane systolic excursion and RV ejection fraction.
- Neonatal hCPC treatment led to decreased RV wall thickness and fibrosis compared to saline-injected controls.
- Computational modeling and in vitro assays revealed superior migration and proliferation capacities of neonatal hCPCs, correlating with enhanced in vivo recruitment.
Conclusions:
- The age of human cardiac progenitor cells (hCPCs) significantly influences their reparative potential in pediatric heart failure.
- Neonatal hCPCs demonstrate superior therapeutic efficacy compared to those from older children in a juvenile heart failure model.
- This study provides crucial insights into age-related stem cell efficacy for advancing stem cell therapy in pediatric cardiovascular regenerative medicine.
Unlabelled:
Children with congenital heart diseases have increased morbidity and mortality, despite various surgical treatments, therefore warranting better treatment strategies. Here we investigate the role of age of human pediatric cardiac progenitor cells (hCPCs) on ventricular remodeling in a model of juvenile heart failure. hCPCs isolated from children undergoing reconstructive surgeries were divided into 3 groups based on age: neonate (1 day to 1 month), infant (1 month to 1 year), and child (1 to 5 years). Adolescent athymic rats were subjected to sham or pulmonary artery banding surgery to generate a model of right ventricular (RV) heart failure. Two weeks after surgery, hCPCs were injected in RV musculature noninvasively. Analysis of cardiac function 4 weeks post-transplantation demonstrated significantly increased tricuspid annular plane systolic excursion and RV ejection fraction and significantly decreased wall thickness and fibrosis in rats transplanted with neonatal hCPCs compared with saline-injected rats. Computational modeling and systems biology analysis were performed on arrays and gave insights into potential mechanisms at the microRNA and gene level. Mechanisms including migration and proliferation assays, as suggested by computational modeling, showed improved chemotactic and proliferative capacity of neonatal hCPCs compared with infant/child hCPCs. In vivo immunostaining further suggested increased recruitment of stem cell antigen 1-positive cells in the right ventricle. This is the first study to assess the role of hCPC age in juvenile RV heart failure. Interestingly, the reparative potential of hCPCs is age-dependent, with neonatal hCPCs exerting the maximum beneficial effect compared with infant and child hCPCs.
Significance:
Stem cell therapy for children with congenital heart defects is moving forward, with several completed and ongoing clinical trials. Although there are studies showing how children differ from adults, few focus on the differences among children. This study using human cardiac progenitor cells shows age-related changes in the reparative ability of cells in a model of pediatric heart failure and uses computational and systems biology to elucidate potential mechanisms.
