Abstract
Newborns with critical congenital heart disease are at significant risk of developing heart failure later in life. Because treatment options for end-stage heart disease in children are limited, regenerative therapies for these patients would be of significant benefit. During neonatal cardiac surgery, a portion of the thymus is removed and discarded. This discarded thymus tissue is a good source of MSCs that we have previously shown to be proangiogenic and to promote cardiac function in an in vitro model of heart tissue. The purpose of this study was to further evaluate the cardiac regenerative and protective properties of neonatal thymus (nt) MSCs. We found that ntMSCs expressed and secreted the proangiogenic and cardiac regenerative morphogen sonic hedgehog (Shh) in vitro more than patient-matched bone-derived MSCs. We also found that organoid culture of ntMSCs stimulated Shh expression. We then determined that ntMSCs were cytoprotective of neonatal rat cardiomyocytes exposed to H2O2. Finally, in a rat left coronary ligation model, we found that scaffoldless cell sheet made of ntMSCs applied to the LV epicardium immediately after left coronary ligation improved LV function, increased vascular density, decreased scar size, and decreased cardiomyocyte death four weeks after infarction. We conclude that ntMSCs have cardiac regenerative properties and warrant further consideration as a cell therapy for congenital heart disease patients with heart failure.
Highlights
Loss of vasculature appears as an important pathophysiological mechanism in heart failure associated with complex congenital heart disease (CHD) [1, 2]
We have previously shown that neonatal thymus mesenchymal stem cells are proangiogenic and can improve systolic function in a “heart in a dish” model [7, 8]
sonic hedgehog (Shh) transcript expression was determined by qPCR in pairs of neonatal thymus mesenchymal stem cells (ntMSCs) and neonatal sternal bone MSCs isolated from 7 patients (Figure 1(a))
Summary
Loss of vasculature appears as an important pathophysiological mechanism in heart failure associated with complex congenital heart disease (CHD) [1, 2]. Open heart surgery in neonates and infants with complex CHD usually requires partial excision of the thymus gland to gain access to the underlying heart and great vessels. We have previously shown that neonatal thymus mesenchymal stem cells (ntMSCs) are proangiogenic and can improve systolic function in a “heart in a dish” model [7, 8]. We found that this improvement was likely due to a paracrine mechanism and that ntMSCs did not differentiate into cardiomyocytes [7]
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