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Translational Profiling of Cardiomyocytes Identifies an Early Jak1/Stat3 Injury Response Required for Zebrafish Heart Regenerati

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Translational Profiling of Cardiomyocytes Identifies an Early Jak1/Stat3 Injury Response Required for Zebrafish Heart Regenerati Translational profiling of cardiomyocytes identifies an early Jak1/Stat3 injury response required for zebrafish heart regeneration Yi Fang, Vikas Gupta, Ravi Karra, Jennifer E. Holdway, Kazu Kikuchi1, and Kenneth D. Poss2 Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710 Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved July 5, 2013 (received for review May 24, 2013) Certain lower vertebrates like zebrafish activate proliferation of we used TRAP to identify ribosome-associated RNAs in spared cardiomyocytes after cardiac injury to regenerate lost zebrafish cardiomyocytes during heart regeneration. heart muscle. Here, we used translating ribosome affinity purifi- cation to profile translating RNAs in zebrafish cardiomyocytes Results during heart regeneration. We identified dynamic induction of To generate cardiomyocyte ribosome-associated RNA profiles several Jak1/Stat3 pathway members following trauma, events from transgenic zebrafish, we used regulatory sequences of accompanied by cytokine production. Transgenic Stat3 inhibition cardiac myosin light chain 2a to drive expression of an EGFP- pd61 in cardiomyocytes restricted injury-induced proliferation and regen- L10a cassette [Tg(cmlc2:EGFP-RPL10a) ] (referred to as eration, but did not reduce cardiogenesis during animal growth. cmlc2:TRAP) (Fig. 1 A and B). Because the cmlc2a promoter is The secreted protein Rln3a was induced in a Stat3-dependent man- active in virtually all adult cardiomyocytes, the cmlc2:TRAP line ner by injury, and exogenous Rln3 delivery during Stat3 inhibition is expected to identify cardiomyocytegeneexpressionduring stimulated cardiomyocyte proliferation. Our results identify an injury- early injury responses as well as regenerative responses. The specific cardiomyocyte program essential for heart regeneration. TRAP reporter was expressed in cardiomyocytes, where its pres- ence did not inhibit heart regeneration (Fig. 1C). To assess the TRAP | cardiac regeneration | interleukin | inflammation | endocardium specificity of this approach, we immunoprecipitated ribosome- associated RNAs from ventricles of adult cmlc2:TRAP fish and examined expression of cardiac genes. These experiments de- ardiac regeneration eludes adult mammals, but certain tected known cardiomyocyte markers by PCR amplification, but nonmammalian vertebrates present models of robust cardiac C genes with expression known to be restricted to other cell types repair. In particular, zebrafish maintain a high capacity for myo- were weak or undetectable (Fig. 1D). cardial regeneration throughout life and can create new heart To profile gene expression after injury, we immunoprecipi- muscle with minimal scarring after a variety of severe genetic or fi – tated cardiomyocyte RNAs from uninjured cmlc2:TRAP sh mechanical injuries (1 3). Thus, studies of how heart regener- ventricles and ventricles at 1 and 7 d after 20% apical resection ation occurs naturally can help guide approaches to stimulating (dpa). The apical halves of ventricles were collected and pooled, adult mammalian heart regeneration, for which there are now and immunoprecipitated RNA was processed for microarray – multiple promising strategies (4 9). analysis. We identified 138 genes with significant expression Genetic fate-mapping experiments indicated that spared car- differences at 1 dpa compared with uninjured ventricles, and fi diomyocytes are the primary source tissue for zebra sh heart fewer differentially expressed genes at 7 dpa (Fig. S1A and Table regeneration, with little or no contribution by a resident stem cell S1; raw data have been deposited in the National Center for population (1, 10–12). Retinoic acid, Transforming growth factor Biotechnology Information Gene Expression Omnibus Web site). beta 1, Insulin-like growth factor 2, Sonic hedgehog, and Platelet- Levels of ion transporters and channels, such as solute carrier derived growth factor ligands all are synthesized in the vicinity of family 39 member 3, chloride intracellular channel 5, solute proliferating cardiomyocytes, and have positive influences on carrier family 12,andpotassium voltage-gated channel subfamily H muscle regeneration (13–16). Other potential factors include member 6, were increased by 1 dpa, supporting previously identi- hypoxia, which appears to play a positive role in cardiomyocyte fied changes in cardiomyocyte electrical properties during re- proliferation, whereas hyperoxia, active p38α mitogen activated generation (1, 11). We also found increased levels of genes protein kinase, and microRNA miR-133 have negative roles (17– relevant to cell survival and proliferation, such as B-cell lymphoma 19). Defining additional pathways that underlie injury-induced 2 (bcl2), jun B proto-oncogene a, FOS-like antigen 1a, poly(ADP- cardiomyocyte proliferation in zebrafish is important for better ribose) polymerase family member 3 and 4 (Fig. S1B). Compared understanding heart regeneration, and is also relevant to new with a published microarray dataset using whole 1-dpa ventric- methodology to boost the low levels of cardiomyocyte proliferation ular tissue (24), only 10 genes with significant expression changes in injured mammalian hearts (20, 21). Novel transgenic profiling technologies have recently been developed for isolation of actively translated mRNAs from Author contributions: Y.F. and K.D.P. designed research; Y.F., V.G., R.K., and J.E.H. per- specific cell types (22, 23). For example, with translating ribo- formed research; Y.F., V.G., and K.K. contributed new reagents/analytic tools; Y.F., R.K., and J.E.H. analyzed data; and Y.F. and K.D.P. wrote the paper. some affinity purification (TRAP) technology, an enhanced GFP fl (EGFP) reporter gene is fused to the N terminus of the large The authors declare no con ict of interest. subunit ribosomal protein L10a, and this cassette is placed This article is a PNAS Direct Submission. downstream of a tissue-specific promoter. Translating mRNAs Data deposition: The raw data reported in this paper has been deposited in the Gene fi Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. can then be isolated from promoter-de ned cell populations in GSE48914). The microarray data can be found in Table S1. transgenic animals by immunoprecipitation with an antibody 1Present address: Developmental and Stem Cell Biology Division, Victor Chang Cardiac recognizing EGFP. Although this technology has not yet been Research Institute, Darlinghurst, NSW, 2010 Australia. applied to tissue regeneration, TRAP avoids tissue dissociation 2To whom correspondence should be addressed. E-mail: [email protected]. fi fi and cell puri cation, and thus has clear advantages for pro ling This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. injury and regeneration responses in specific cell types. Here, 1073/pnas.1309810110/-/DCSupplemental. 13416–13421 | PNAS | August 13, 2013 | vol. 110 | no. 33 www.pnas.org/cgi/doi/10.1073/pnas.1309810110 Downloaded by guest on October 1, 2021 Fig. 1. Translational profiling of cardiomyocytes during zebrafish heart regeneration. (A)Tissuesec- tion indicating localization of EGFP-L10a fluorescence to cardiomyocytes in cmlc2:TRAP hearts. (B)Higher- magnification view of an uninjured cmlc2:TRAP ventricular apex. (C) Regeneration appears normal in cmlc2:TRAP ventricles 30 d after partial resection. Dashed line indicates approximate amputation plane. (Scale bars for A–C,50μm.) (D) RT-PCR of total or immunoprecipitated (TRAP) RNAs iso- lated from adult cmlc2:TRAP ventricles. β-actin1, hand2, cmlc2, ventricular myosin heavy chain (vmhc) and anf (also known as natriuretic peptide precursor A) are expressed in cardiomyocytes (CMs), and flk1 (endocardial), gata2a (hematopoietic), and tcf21 (epicardial) are noncardiomyocyte genes (Non- CMs). (E) Heat map from microarray indicating in- creased levels of Jak1/Stat3 pathway members in cmlc2:TRAP RNA samples at 1 dpa. (F) qPCR using RNAs immunoprecipitated from cmlc2:TRAP ven- tricles, confirming up-regulation of Jak1/Stat3 path- way members after injury. Expression levels were normalized to that of β-actin2, and further nor- malized to that of the uninjured sample. Data are mean ± SEM n = 3, *P < 0.05, **P < 0.01, ***P < 0.001, Student t test (unpaired, two-tailed). (G) Western Blots using total proteins extracted from uninjured and 1-dpa hearts, indicating increased protein levels of Stat3, phosphorylated Stat3 (P-Stat3), and Bcl2 at 1 dpa. Tubulin was used as a loading control (shown for Stat3 and P-Stat3 lanes). are shared. Possible explanations for this modest overlap in- proliferation, and other events (28, 29). Pathway up-regulation BIOLOGY clude: (i) background noise from gene-expression changes in was further confirmed by in situ hybridization. Similar to dy- DEVELOPMENTAL nonmuscle cells; (ii)specificity of the TRAP technique to ri- namic expression signatures of certain epicardial and endocar- bosome-associated RNAs; and (iii) variation in gene coverage dial factors (15, 30), induction of Jak1/Stat3 pathway genes was among microarrays. TRAP did not identify some genes pre- first organ-wide at 1 dpa, but then localized to a region of car- viously detected by visual techniques in cardiomyocytes at 7 diomyocytes at the site of regeneration by 7 dpa (Fig. 2 A and B, dpa, such as gata4 and mps1 (3,11).Wesuspectthatthis and Fig. S2A). finding is at least in part a result of dilution of signals by Many ligands transduce signaling
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