Nkx2.5+ Cardiomyoblasts Contribute to Cardiomyogenesis in the Neonatal Heart

Overview

Journal Sci Rep

Specialty Science

Date 2017 Oct 5

PMID 28974782

Citations 21

Authors

Vahid Serpooshan

Yuan-Hung Liu

Jan W Buikema

Francisco X Galdos

Orlando Chirikian

Sharon Paige

Sneha Venkatraman

Anusha Kumar

David R Rawnsley

Xiaojing Huang

Daniel A Pijnappels

Sean M Wu

Affiliations

Soon will be listed here.

Abstract

During normal lifespan, the mammalian heart undergoes limited renewal of cardiomyocytes. While the exact mechanism for this renewal remains unclear, two possibilities have been proposed: differentiated myocyte replication and progenitor/immature cell differentiation. This study aimed to characterize a population of cardiomyocyte precursors in the neonatal heart and to determine their requirement for cardiac development. By tracking the expression of an embryonic Nkx2.5 cardiac enhancer, we identified cardiomyoblasts capable of differentiation into striated cardiomyocytes in vitro. Genome-wide expression profile of neonatal Nkx2.5+ cardiomyoblasts showed the absence of sarcomeric gene and the presence of cardiac transcription factors. To determine the lineage contribution of the Nkx2.5+ cardiomyoblasts, we generated a doxycycline suppressible Cre transgenic mouse under the regulation of the Nkx2.5 enhancer and showed that neonatal Nkx2.5+ cardiomyoblasts mature into cardiomyocytes in vivo. Ablation of neonatal cardiomyoblasts resulted in ventricular hypertrophy and dilation, supporting a functional requirement of the Nkx2.5+ cardiomyoblasts. This study provides direct lineage tracing evidence that a cardiomyoblast population contributes to cardiogenesis in the neonatal heart. The cell population identified here may serve as a promising therapeutic for pediatric cardiac regeneration.

Citing Articles

Gastrulation-stage gene expression in mouse embryos foreshadows the development of syndromic birth defects.

Chea S, Kreger J, Lopez-Burks M, MacLean A, Lander A, Calof A Sci Adv. 2024; 10(12):eadl4239.

PMID: 38507484 PMC: 10954218. DOI: 10.1126/sciadv.adl4239.

Nkx2.5: a crucial regulator of cardiac development, regeneration and diseases.

Cao C, Li L, Zhang Q, Li H, Wang Z, Wang A Front Cardiovasc Med. 2023; 10:1270951.

PMID: 38124890 PMC: 10732152. DOI: 10.3389/fcvm.2023.1270951.

The benign nature and rare occurrence of cardiac myxoma as a possible consequence of the limited cardiac proliferative/ regenerative potential: a systematic review.

Shafi O, Siddiqui G, Jaffry H BMC Cancer. 2023; 23(1):1245.

PMID: 38110859 PMC: 10726542. DOI: 10.1186/s12885-023-11723-3.

Leveraging 3D Bioprinting and Photon-Counting Computed Tomography to Enable Noninvasive Quantitative Tracking of Multifunctional Tissue Engineered Constructs.

Gil C, Evans C, Li L, Allphin A, Tomov M, Jin L Adv Healthc Mater. 2023; 12(31):e2302271.

PMID: 37709282 PMC: 10842604. DOI: 10.1002/adhm.202302271.

Nucleosome proteostasis and histone turnover.

Arrieta A, Vondriska T Front Mol Biosci. 2022; 9:990006.

PMID: 36250018 PMC: 9563994. DOI: 10.3389/fmolb.2022.990006.

References

Hsueh Y, Wu J, Yu C, Wu K, Hsieh P . Prostaglandin E₂ promotes post-infarction cardiomyocyte replenishment by endogenous stem cells. EMBO Mol Med. 2014; 6(4):496-503. PMC: 3992076. DOI: 10.1002/emmm.201303687. View

Olson E, Schneider M . Sizing up the heart: development redux in disease. Genes Dev. 2003; 17(16):1937-56. DOI: 10.1101/gad.1110103. View

Ivanova A, Signore M, Caro N, Greene N, Copp A, Martinez-Barbera J . In vivo genetic ablation by Cre-mediated expression of diphtheria toxin fragment A. Genesis. 2005; 43(3):129-35. PMC: 2233880. DOI: 10.1002/gene.20162. View

Kattman S, Witty A, Gagliardi M, Dubois N, Niapour M, Hotta A . Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell. 2011; 8(2):228-40. DOI: 10.1016/j.stem.2010.12.008. View

Jopling C, Sleep E, Raya M, Marti M, Raya A, Izpisua Belmonte J . Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010; 464(7288):606-9. PMC: 2846535. DOI: 10.1038/nature08899. View

Zohlnhofer D, Ott I, Mehilli J, Schomig K, Michalk F, Ibrahim T . Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA. 2006; 295(9):1003-10. DOI: 10.1001/jama.295.9.1003. View

Lien C, Wu C, Mercer B, Webb R, Richardson J, Olson E . Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer. Development. 1998; 126(1):75-84. DOI: 10.1242/dev.126.1.75. View

Kuhn B, Monte F, Hajjar R, Chang Y, Lebeche D, Arab S . Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med. 2007; 13(8):962-9. DOI: 10.1038/nm1619. View

Porrello E, Olson E . A neonatal blueprint for cardiac regeneration. Stem Cell Res. 2014; 13(3 Pt B):556-70. PMC: 4316722. DOI: 10.1016/j.scr.2014.06.003. View

10.

Wu S, Chien K, Mummery C . Origins and fates of cardiovascular progenitor cells. Cell. 2008; 132(4):537-43. PMC: 2507768. DOI: 10.1016/j.cell.2008.02.002. View

11.

Lepilina A, Coon A, Kikuchi K, Holdway J, Roberts R, Burns C . A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell. 2006; 127(3):607-19. DOI: 10.1016/j.cell.2006.08.052. View

12.

Smith C, Baek S, Sung C, Tallquist M . Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling. Circ Res. 2011; 108(12):e15-26. PMC: 3134964. DOI: 10.1161/CIRCRESAHA.110.235531. View

13.

Kikuchi K, Gupta V, Wang J, Holdway J, Wills A, Fang Y . tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration. Development. 2011; 138(14):2895-902. PMC: 3119303. DOI: 10.1242/dev.067041. View

14.

Pashmforoush M, Lu J, Chen H, St Amand T, Kondo R, Pradervand S . Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell. 2004; 117(3):373-86. DOI: 10.1016/s0092-8674(04)00405-2. View

15.

Bergmann O, Bhardwaj R, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S . Evidence for cardiomyocyte renewal in humans. Science. 2009; 324(5923):98-102. PMC: 2991140. DOI: 10.1126/science.1164680. View

16.

Abel E, Kaulbach H, Tian R, Hopkins J, Duffy J, Doetschman T . Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. J Clin Invest. 1999; 104(12):1703-14. PMC: 409881. DOI: 10.1172/JCI7605. View

17.

Kuhn E, Wu S . Origin of cardiac progenitor cells in the developing and postnatal heart. J Cell Physiol. 2010; 225(2):321-5. PMC: 3620291. DOI: 10.1002/jcp.22281. View

18.

Ehler E, Moore-Morris T, Lange S . Isolation and culture of neonatal mouse cardiomyocytes. J Vis Exp. 2013; (79). PMC: 3857885. DOI: 10.3791/50154. View

19.

Abdel-Latif A, Bolli R, Tleyjeh I, Montori V, Perin E, Hornung C . Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007; 167(10):989-97. DOI: 10.1001/archinte.167.10.989. View

20.

Sun Y, Liang X, Najafi N, Cass M, Lin L, Cai C . Islet 1 is expressed in distinct cardiovascular lineages, including pacemaker and coronary vascular cells. Dev Biol. 2007; 304(1):286-96. PMC: 2582044. DOI: 10.1016/j.ydbio.2006.12.048. View