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Developmental biology - Heart

Sequencing Cardiac Cell RNA Reveals Secrets

Massively parallel single-nucleus sequencing offers a key tool in cardiac biology and heart disease...


Using a powerful new technology that sequences RNA in 20,000 individual cell nuclei, scientists have uncovered new insights into heart disease. In animal studies, researchers identified a broad variety of cell types in both healthy and diseased hearts, and investigated in rich detail a "transcriptional landscape" where DNA transfers genetic information into RNA and proteins.
"This is the first time to our knowledge that massively parallel single-nucleus RNA sequencing has been applied to postnatal mouse hearts, providing a wealth of detail about biological events in both normal heart development and heart disease. Ultimately, our goal is to use this knowledge to develop targeted treatments for heart disease. In addition, this type of large-scale sequencing may be broadly applied in many other fields of medicine."

Liming Pei PhD, Molecular Biologist, Center for Mitochondrial and Epigenomic Medicine (CMEM), Children's Hospital of Philadelphia (CHOP); Assistant Professor, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, USA.

Pei and co-study leader Hao Wu PhD, also of the CMEM and an assistant professor of Genetics at Penn Medicine, published their findings online Sept. 25, 2018 in Genes & Development.

While massively parallel single-cell RNA sequencing (scRNA-seq) has been available to researchers for three years, it is technically challenging to study single cells in postnatal hearts due to the large size of cardiac muscle cells.

To enable single-cell analysis of large cells such as muscle cells, or cells with complex morphology such as neurons, robust massively parallel single-nucleus sequencing (snRNA-seq) methods have been developed recently in Hao Wu's laboratory, as well as by others in the field.
To date, massively parallel snRNA-seq has been applied only to the central nervous system. Pei and colleagues are the first to adapt the technology for use in postnatal heart tissue.

The research team used the snRNA-Seq method termed sNucDrop-seq to analyze nearly 20,000 nuclei in heart tissue from normal and diseased mice. "We are excited to further develop sNucDrop-seq and apply it to mammalian postnatal hearts, which are of critical medical relevance but difficult to study with standard scRNA-seq," explains Wu.

The current study focuses on cardiomyopathy, a group of diseases characterized by progressive weakening of the heart muscle, and represents a leading worldwide cause of heart failure. Pei and colleagues used mice developed to model a type of pediatric mitochondrial cardiomyopathy.
"The heart is a complex organ, with a multitude of cell types, and much still remains poorly understood about mammalian heart development and heart disease - especially during the postnatal period. Our study provides key insights in three areas: normal heart development, heart disease, and gene regulatory mechanisms of a heart hormone called GDF15."

Liming Pei PhD

Sequencing identified major types of heart cells - cardiomyocytes, fibroblasts and endothelial cells, as well as some rarer cardiac cell types - with functional changes in both normal and diseased cells. In one example they detected metabolic changes in fibroblast cells that go one to make the heart abnormally stiff when diseased.
Another finding concerned gene networks regulating production of cardiac hormones - specifically GDF15 - which slows overall body growth in a presumed attempt to reduce energy demands on a damaged heart. This signaling could reveal more about biological mechanisms underlying growth restrictions commonly seen in children with congenital heart disease.

Greater understanding of cardiac biology, as provided in this research, said Pei, may lead to targeted therapies aimed at key gene networks that could offer better treatments for heart patients. Future work will investigate how heart disease progresses over a longer timespan than the early postnatal period.

Abstract
A fundamental challenge in understanding cardiac biology and disease is that the remarkable heterogeneity in cell type composition and functional states have not been well characterized at single-cell resolution in maturing and diseased mammalian hearts. Massively parallel single-nucleus RNA sequencing (snRNA-seq) has emerged as a powerful tool to address these questions by interrogating the transcriptome of tens of thousands of nuclei isolated from fresh or frozen tissues. snRNA-seq overcomes the technical challenge of isolating intact single cells from complex tissues, including the maturing mammalian hearts; reduces biased recovery of easily dissociated cell types; and minimizes aberrant gene expression during the whole-cell dissociation. Here we applied sNucDrop-seq, a droplet microfluidics-based massively parallel snRNA-seq method, to investigate the transcriptional landscape of postnatal maturing mouse hearts in both healthy and disease states. By profiling the transcriptome of nearly 20,000 nuclei, we identified major and rare cardiac cell types and revealed significant heterogeneity of cardiomyocytes, fibroblasts, and endothelial cells in postnatal developing hearts. When applied to a mouse model of pediatric mitochondrial cardiomyopathy, we uncovered profound cell type-specific modifications of the cardiac transcriptional landscape at single-nucleus resolution, including changes of subtype composition, maturation states, and functional remodeling of each cell type. Furthermore, we employed sNucDrop-seq to decipher the cardiac cell type-specific gene regulatory network (GRN) of GDF15, a heart-derived hormone and clinically important diagnostic biomarker of heart disease. Together, our results present a rich resource for studying cardiac biology and provide new insights into heart disease using an approach broadly applicable to many fields of biomedicine.

Authors
Peng Hu1, Jian Liu1, Juanjuan Zhao1, Benjamin J. Wilkins, Katherine Lupino, Hao Wu and Liming Pei.


Acknowledgements
The National Institutes of Health (grants DK111495, HG007982, HL142044, and DK099379) and Department of Defense grant W81XWH-16-1-0400 supported this research, along with the W.W. Smith Charitable Trust.

Peng Hu, et al, "Single-nucleus transcriptomic survey of cell diversity and functional maturation in postnatal mammalian hearts," Genes & Development, online Sept. 25, 2018. http://doi.org/10.1101/gad.316802.118

About Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 546-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu


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Oct 12, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




RNA analysis of 20,000 cardiac cells from heart tissue of both ordinary and deceased mice gave insight on the development of heart disease and a gene regulatory mechanism heart hormone called GDF15.


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