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JCI Insight. 2019 Nov 14;4(22). pii: 131092. doi: 10.1172/jci.insight.131092.

Transcriptional heterogeneity of fibroblasts is a hallmark of the aging heart.

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Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Berlin Institute of Health, Berlin, Germany.
Faculty for Biological Sciences and.
Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany.
Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
St. Vincent's Clinical School, University of New South Wales Sydney, Kensington, New South Wales, Australia.
Cardiopulmonary Institute, Goethe University Frankfurt, Frankfurt, Germany.
School of Biotechnology and Biomolecular Science, University of New South Wales Sydney, Kensington, New South Wales, Australia.
German Centre for Cardiovascular Research, Berlin, Germany.


Aging is a major risk factor for cardiovascular disease. Although the impact of aging has been extensively studied, little is known regarding the aging processes in cells of the heart. Here we analyzed the transcriptomes of hearts of 12-week-old and 18-month-old mice by single-nucleus RNA-sequencing. Among all cell types, aged fibroblasts showed most significant differential gene expression, increased RNA dynamics, and network entropy. Aged fibroblasts exhibited significantly changed expression patterns of inflammatory, extracellular matrix organization angiogenesis, and osteogenic genes. Functional analyses indicated deterioration of paracrine signatures between fibroblasts and endothelial cells in old hearts. Aged heart-derived fibroblasts had impaired endothelial cell angiogenesis and autophagy and augmented proinflammatory response. In particular, expression of Serpine1 and Serpine2 were significantly increased and secreted by old fibroblasts to exert antiangiogenic effects on endothelial cells, an effect that could be significantly prevented by using neutralizing antibodies. Moreover, we found an enlarged subpopulation of aged fibroblasts expressing osteoblast genes in the epicardial layer associated with increased calcification. Taken together this study provides system-wide insights and identifies molecular changes of aging cardiac fibroblasts, which may contribute to declined heart function.


Aging; Cardiology; Heart failure; Molecular biology; Serpins

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