27 Jan Reduced Stem Cells Link Congenital Heart Disease To Impaired Brain Growth

MedicalResearch.com Interview with:

Children’s National Research Team

Paul D. Morton, Ph.D.
Research PostDoc and lead study author of “Abnormal Neurogenesis and Cortical Growth in Congenital Heart Disease.”
Children’s National Health System Washington, DC

Nobuyuki Ishibashi, M.D.
Director of the Cardiac Surgery Research Laboratory at Children’s National Health System and co-senior study author.

Vittorio Gallo, Ph.D.
Director of the Center for Neuroscience Research at Children’s National Health System and co-senior study author.

Richard A. Jonas, M.D.
Chief of the Division of Cardiac Surgery at Children’s National Health System and co-senior study author.

MedicalResearch.com: What is the background for this study?

Response: Congenital heart disease (CHD) is the leading birth defect in the United States and often results in an array of long-term neurological deficits including motor, cognitive and behavioral abnormalities. It has become increasingly clear that children with CHD often have underdeveloped brains. In many cases of complex CHD, blood flow to the brain is both reduced and less oxygenated, which has been associated with developmental abnormalities and delay. The cellular mechanisms underlying the impact of CHD on brain development remain largely unknown. We developed a preclinical chronic hypoxia model to define these mechanisms.

MedicalResearch.com: What are the main findings?

Response: Our model of congenital heart disease recapitulates key signatures seen in the clinic, including a reduction in cortical volume and cortical folding. We identified key hubs of neural stem/progenitor cells (NSPCs) within the subventricular zone (SVZ) that supply the postnatal preclinical model’s cortex with newborn neurons and interneurons. Our preclinical model demonstrates that select pools of NSPCs are particularly vulnerable to hypoxia in that there are fewer of them and they display a reduced renewal capacity. In addition, we found a drastic decline in neuroblasts within select regions of the SVZ. Consistent with our findings in the pre-clinical model, we also found a reduction in neuroblast numbers as well as disruption of the SVZ cytoarchitecture in postmortem brain specimens from CHD newborns. Finally, in our preclinical model, we found region-specific reductions in immature neurons and mature neurons and interneurons primarily in the prefrontal cortex.

MedicalResearch.com: What should readers take away from your report?

Response: SVZ-NSPCs contribute to cortical growth following birth and this highly vascularized region is disrupted in cases of complex CHD that are associated with reduced cerebral blood flow. Therefore, treatments designed to restore the growth capacity of these key cell pools may improve brain development in congenital heart disease.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: The next main goal is to define the molecular mechanism(s) underlying the cellular response to congenital heart disease. Identifying such mechanisms will bring us a step closer to developing drugs or treatment strategies to prevent or reverse these effects. In addition, longitudinal and behavioral studies will be important in determining long-term outcomes in our preclinical model.

MedicalResearch.com: Is there anything else you would like to add?

Response: Financial support for this work was provided by the National Institutes of Health, the Intellectual and Developmental Disabilities Research Center, the Baier Cardiac Research Fund, the Children’s Heart Foundation, the Children’s Research Institute Neonatal Brain Injury Project and the Foglia and Hills families.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:
Abnormal neurogenesis and cortical growth in congenital heart disease
BY PAUL D. MORTON, LUDMILA KOROTCOVA, BOBBI K. LEWIS, SHIVAPRASAD BHUVANENDRAN, SHRUTI D. RAMACHANDRA, DAVID ZURAKOWSKI, JIANGYANG ZHANG, SUSUMU MORI, JOSEPH A. FRANK, RICHARD A. JONAS, VITTORIO GALLO, NOBUYUKI ISHIBASHI
SCIENCE TRANSLATIONAL MEDICINE25 JAN 2017
Congenital heart disease depletes SVZ neural stem/progenitor cell pools critical for normal cortical growth.

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Last Updated on January 27, 2017 by Marie Benz MD FAAD