Xingbo Xu1, Ingeborg Friehs1, Tachi Zhong Hu1, Ivan Melnychenko1, Björn Tampe1, Fouzi Alnour1, Maria Iascone1, Raghu Kalluri1, Michael Zeisberg1, Pedro J Del Nido1, Elisabeth M Zeisberg2. 1. From the Department of Cardiology and Pneumology (X.X., F.A., E.M.Z.), Department of Nephrology and Rheumatology (B.T., M.Z.), University Medical Center of Göttingen, Georg-August University, Göttingen, Germany; Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, MA (I.F., I.V., P.J.d N.); Division of Matrix Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (T.Z.H., R.K., E.M.Z.); Lab Genetica Molecolare, Papa Giovanni XXIII Hospital, Bergamo, Italy (M.I.); Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston (R.K.); and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany (E.M.Z.). 2. From the Department of Cardiology and Pneumology (X.X., F.A., E.M.Z.), Department of Nephrology and Rheumatology (B.T., M.Z.), University Medical Center of Göttingen, Georg-August University, Göttingen, Germany; Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, MA (I.F., I.V., P.J.d N.); Division of Matrix Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (T.Z.H., R.K., E.M.Z.); Lab Genetica Molecolare, Papa Giovanni XXIII Hospital, Bergamo, Italy (M.I.); Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston (R.K.); and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany (E.M.Z.). Elisabeth.zeisberg@med.uni-goettingen.de.
Abstract
RATIONALE: Endocardial fibroelastosis (EFE) is a unique form of fibrosis, which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through the establishment of staged biventricular repair surgery in infant patients with hypoplastic left heart syndrome, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to the growth of the left ventricle in parallel with somatic growth. However, pathomechanisms underlying EFE formation are still scarce, and specific therapeutic targets are not yet known. OBJECTIVE: Here, we aimed to investigate the cellular origins of EFE tissue and to gain insights into the underlying molecular mechanisms to ultimately develop novel therapeutic strategies. METHODS AND RESULTS: By utilizing a novel EFE model of heterotopic transplantation of hearts from newborn reporter mice and by analyzing human EFE tissue, we demonstrate for the first time that fibrogenic cells within EFE tissue originate from endocardial endothelial cells via aberrant endothelial to mesenchymal transition. We further demonstrate that such aberrant endothelial to mesenchymal transition involving endocardial endothelial cells is caused by dysregulated transforming growth factor beta/bone morphogenetic proteins signaling and that this imbalance is at least in part caused by aberrant promoter methylation and subsequent transcriptional suppression of bone morphogenetic proteins 5 and 7. Finally, we provide evidence that supplementation of exogenous recombinant bone morphogenetic proteins 7 effectively ameliorates endothelial to mesenchymal transition and experimental EFE in rats. CONCLUSIONS: In summary, our data point to aberrant endothelial to mesenchymal transition as a common denominator of infant EFE development in heterogeneous, congenital heart diseases, and to bone morphogenetic proteins 7 as an effective treatment for EFE and its restriction of heart growth.
RATIONALE: Endocardial fibroelastosis (EFE) is a unique form of fibrosis, which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through the establishment of staged biventricular repair surgery in infantpatients with hypoplastic left heart syndrome, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to the growth of the left ventricle in parallel with somatic growth. However, pathomechanisms underlying EFE formation are still scarce, and specific therapeutic targets are not yet known. OBJECTIVE: Here, we aimed to investigate the cellular origins of EFE tissue and to gain insights into the underlying molecular mechanisms to ultimately develop novel therapeutic strategies. METHODS AND RESULTS: By utilizing a novel EFE model of heterotopic transplantation of hearts from newborn reporter mice and by analyzing humanEFE tissue, we demonstrate for the first time that fibrogenic cells within EFE tissue originate from endocardial endothelial cells via aberrant endothelial to mesenchymal transition. We further demonstrate that such aberrant endothelial to mesenchymal transition involving endocardial endothelial cells is caused by dysregulated transforming growth factor beta/bone morphogenetic proteins signaling and that this imbalance is at least in part caused by aberrant promoter methylation and subsequent transcriptional suppression of bone morphogenetic proteins 5 and 7. Finally, we provide evidence that supplementation of exogenous recombinant bone morphogenetic proteins 7 effectively ameliorates endothelial to mesenchymal transition and experimental EFE in rats. CONCLUSIONS: In summary, our data point to aberrant endothelial to mesenchymal transition as a common denominator of infantEFE development in heterogeneous, congenital heart diseases, and to bone morphogenetic proteins 7 as an effective treatment for EFE and its restriction of heart growth.
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