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| Status |
Public on Dec 24, 2019 |
| Title |
Single-cell analysis uncovers that metabolic reprogramming is essential for cardiomyocyte proliferation in the regenerating heart. |
| Organism |
Danio rerio |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
While the heart regenerates poorly in mammals, efficient heart regeneration occurs in certain amphibian and fish species. Zebrafish has been used extensively to study heart regeneration, resulting in a model in which preexisting cardiomyocytes dedifferentiate and reinitiate proliferation to replace the lost myocardium. However, there is limited knowledge about the cellular processes that occur in this rare population of proliferating cardiomyocytes during heart regeneration. To identify such processes, we generated a transgenic line based on nppa expression that marks proliferating cardiomyocytes located at the wound border zone. Next we have used a single-cell RNA-sequencing approach in the regenerating adult zebrafish heart and we uncovered that proliferating border zone cardiomyocytes have very distinct transcriptomes compared to the non-proliferating remote cardiomyocytes and that they resemble embryonic cardiomyocytes. Moreover, these cells have reduced expression of mitochondrial genes and reduced mitochondrial oxidative phosphorylation activity, while glycolysis gene expression and glucose uptake are increased, indicative for metabolic reprogramming. Mechanistically, this metabolic reprogramming is induced by Nrg1/Erbb2 signaling and this mechanism is conserved in murine hearts. Furthermore, pharmacological inhibition of glycolysis impairs cardiomyocyte proliferation of both zebrafish and murine cardiomyocytes. Together these results reveal a conserved mechanism in which cardiomyocytes undergo metabolic reprogramming, which is essential for cardiomyocyte proliferation and heart regeneration and could ultimately help to develop novel methods to promote mammalian heart repair.
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| Overall design |
Tg(nppa:mCitrine) positive cells (n=576) were collected from 13 cryoinjured hearts. As an internal control, also nppa negative cells were sorted. (n=192). In addition Tg(myl7:GFP) positive cells (n=768) were sorted from 2dpf embryos. All cells were sent for single cell RNA sequencing.
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| Contributor(s) |
Honkoop H, de Bakker DE, Aharonov A, Kruse F, Shakked A, Nguyen PD, de Heus C, Garric L, Muraro MJ, Shoffner A, Tessadori F, Peterson JC, Noort W, Bertozzi A, Weidinger G, Posthuma G, Grün D, van der Laarse WJ, Klumperman J, Jaspers RT, Poss KD, van Oudenaarden A, Tzahor E, Bakkers J |
| Citation(s) |
31868166 |
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| Submission date |
Oct 21, 2019 |
| Last update date |
Feb 10, 2020 |
| Contact name |
Hessel Honkoop |
| E-mail(s) |
h.honkoop@hubrecht.eu
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| Organization name |
Hubrecht Institute
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| Lab |
Bakkers
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| Street address |
Uppsalalaan 8
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| City |
Utrecht |
| State/province |
Zuid-Holland |
| ZIP/Postal code |
3584CT |
| Country |
Netherlands |
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| Platforms (1) |
| GPL20828 |
Illumina NextSeq 500 (Danio rerio) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA578764 |
| SRA |
SRP226527 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE139218_RAW.tar |
3.7 Mb |
(http)(custom) |
TAR (of CSV, TSV) |
| GSE139218_cel-seq2_barcodes.csv.gz |
2.1 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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