Multicellular Transcriptional Analysis of Mammalian Heart Regeneration

被引:205
作者
Quaife-Ryan, Gregory A. [1 ]
Sim, Choon Boon [1 ]
Ziemann, Mark [2 ,3 ]
Kaspi, Antony [2 ,3 ]
Rafehi, Haloom [2 ,3 ]
Ramialison, Mirana [4 ]
El-Osta, Assam [2 ,3 ,5 ]
Hudson, James E. [1 ]
Porrello, Enzo R. [1 ,6 ,7 ]
机构
[1] Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia
[2] Baker Heart & Diabet Inst, Melbourne, Vic, Australia
[3] Monash Univ, Cent Clin Sch, Melbourne, Vic, Australia
[4] Monash Univ, Australian Regenerat Med Inst, EMBL Australia Collaborating Grp, Syst Biol Inst Australia, Melbourne, Vic, Australia
[5] Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Prince Wales Hosp, Hong Kong, Hong Kong, Peoples R China
[6] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia
[7] Royal Childrens Hosp, Dept Physiol, Sch Biomed Sci, Melbourne, Vic, Australia
基金
澳大利亚研究理事会; 英国医学研究理事会;
关键词
ATAC-seq; cell proliferation; epigenomics; muscle cells; myocardial infarction; regeneration; transcriptional profiling; NEONATAL MOUSE HEART; CELL-CYCLE ARREST; CARDIAC REGENERATION; GENE-EXPRESSION; CARDIOMYOCYTE PROLIFERATION; DEDIFFERENTIATION; FIBROBLASTS; MACROPHAGES; CONTRIBUTE; REPAIR;
D O I
10.1161/CIRCULATIONAHA.117.028252
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1123 / +
页数:49
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