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Multicellular transcriptional analysis of mammalian heart regeneration

Quaife-Ryan, Gregory A., Sim, Choon Boon, Ziemann, Mark, Kaspi, Antony, Rafehi, Haloom, Ramialison, Mirana, El-Osta, Assam, Hudson, James E. and Porrello, Enzo R. 2017, Multicellular transcriptional analysis of mammalian heart regeneration, Circulation, vol. 136, no. 12, pp. 1123-1139, doi: 10.1161/CIRCULATIONAHA.117.028252.

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Title Multicellular transcriptional analysis of mammalian heart regeneration
Author(s) Quaife-Ryan, Gregory A.
Sim, Choon Boon
Ziemann, MarkORCID iD for Ziemann, Mark orcid.org/0000-0002-7688-6974
Kaspi, Antony
Rafehi, Haloom
Ramialison, Mirana
El-Osta, Assam
Hudson, James E.
Porrello, Enzo R.
Journal name Circulation
Volume number 136
Issue number 12
Start page 1123
End page 1139
Total pages 17
Publisher Lippincott Williams & Wilkins
Place of publication Philadelphia, Pa.
Publication date 2017-09-19
ISSN 1524-4539
Keyword(s) ATAC-seq
cell proliferation
epigenomics
muscle cells
myocardial infarction
regeneration
transcriptional profiling
Animals
Animals, Newborn
Fibroblasts
Gene Expression Profiling
Gene Expression Regulation, Developmental
Gene Regulatory Networks
Heart
Leukocytes
Mice
Myocytes, Cardiac
RNA
Sequence Analysis, RNA
Signal Transduction
Transcription Factors
Transcriptome
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Peripheral Vascular Disease
Cardiovascular System & Cardiology
NEONATAL MOUSE HEART
CELL-CYCLE ARREST
CARDIAC REGENERATION
GENE-EXPRESSION
CARDIOMYOCYTE PROLIFERATION
DEDIFFERENTIATION
MACROPHAGES
CONTRIBUTE
REPAIR
Summary BACKGROUND: The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we assemble a transcriptomic framework of multiple cardiac cell populations during postnatal development and following injury, which enables comparative analyses of the regenerative (neonatal) versus nonregenerative (adult) state for the first time.

METHODS: Cardiomyocytes, fibroblasts, leukocytes, and endothelial cells from infarcted and noninfarcted neonatal (P1) and adult (P56) mouse hearts were isolated by enzymatic dissociation and fluorescence-activated cell sorting at day 3 following surgery. RNA sequencing was performed on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair, and regeneration. To complement our transcriptomic data, we also surveyed the epigenetic landscape of cardiomyocytes during postnatal maturation by performing deep sequencing of accessible chromatin regions by using the Assay for Transposase-Accessible Chromatin from purified mouse cardiomyocyte nuclei (P1, P14, and P56).

RESULTS: Profiling of cardiomyocyte and nonmyocyte transcriptional programs uncovered several injury-responsive genes across regenerative and nonregenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state. In contrast, cardiomyocytes failed to reactivate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during postnatal maturation.

CONCLUSIONS: This work provides a comprehensive framework and transcriptional resource of multiple cardiac cell populations during cardiac development, repair, and regeneration. Our findings define a regulatory program underpinning the neonatal regenerative state and identify alterations in the chromatin landscape that could limit reinduction of the regenerative program in adult cardiomyocytes.
Language eng
DOI 10.1161/CIRCULATIONAHA.117.028252
Field of Research 1103 Clinical Sciences
1102 Cardiovascular Medicine And Haematology
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2017, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution Non-Commercial No-Derivatives licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30113063

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.