Multi-Investigator Letter on Reproducibility of Neonatal Heart Regeneration following Apical Resection

Abstract

We appreciate the interest that Andersen et al., 2014Andersen D.C. Ganesalingam S. Jensen C.H. Sheikh S.P. Stem Cell Rep. 2014; 2: 406-413Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar have shown in our work on neonatal cardiac regeneration. Their recent paper relates directly to resection methodology first presented by Porrello et al., 2011Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. Sadek H.A. Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1572) Google Scholar and describes a failure to reproduce the observations made in that study regarding regeneration after resection. We are puzzled by the results and conclusion because in the hands of the seven different groups who authored this letter, this methodology has proved robust and reproducible and has been used in several ongoing studies across our different laboratories that are in various stages of completion (Heallen et al., 2013Heallen T. Morikawa Y. Leach J. Tao G. Willerson J.T. Johnson R.L. Martin J.F. Development. 2013; 140: 4683-4690Crossref PubMed Scopus (280) Google Scholar, as well as studies by the Lee, Takeuchi, and Nei groups that are currently under review). Importantly, several independent groups had similar observations using various types of neonatal injury (Strungs et al., 2013Strungs E.G. Ongstad E.L. O’Quinn M.P. Palatinus J.A. Jourdan L.J. Gourdie R.G. Methods Mol. Biol. 2013; 1037: 343-353Crossref PubMed Scopus (42) Google Scholar, Haubner et al., 2012Haubner B.J. Adamowicz-Brice M. Khadayate S. Tiefenthaler V. Metzler B. Aitman T. Penninger J.M. Aging. 2012; 4: 966-977Crossref PubMed Scopus (152) Google Scholar, Naqvi et al., 2014Naqvi N. Li M. Calvert J.W. Tejada T. Lambert J.P. Wu J. Kesteven S.H. Holman S.R. Matsuda T. Lovelock J.D. et al.Cell. 2014; 157: 795-807Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, Jesty et al., 2012Jesty S.A. Steffey M.A. Lee F.K. Breitbach M. Hesse M. Reining S. Lee J.C. Doran R.M. Nikitin A.Y. Fleischmann B.K. Kotlikoff M.I. Proc. Natl. Acad. Sci. USA. 2012; 109: 13380-13385Crossref PubMed Scopus (175) Google Scholar), where an increase in cardiomyocytes was also observed. Having carefully examined the study published by Andersen et al., 2014Andersen D.C. Ganesalingam S. Jensen C.H. Sheikh S.P. Stem Cell Rep. 2014; 2: 406-413Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, it is our overall impression that methodological differences are likely to account for the difference in published results. Although it is difficult to draw clear conclusions about such differences without a detailed analysis of primary data, our impression is that variations in surgical technique, amount of resected myocardium, methods of quantification of resected and regenerated myocardium, and methods of assessment of myocyte proliferation form the basis of the differences seen. In particular, we used ventricular weight and surface area immediately after resection and 21 days later to assess the degree of injury and regeneration, while the Andersen group used HW/BW immediately after resection and ventricular weight 21 days later. Notably, in Figure 1E of the Andersen et al., 2014Andersen D.C. Ganesalingam S. Jensen C.H. Sheikh S.P. Stem Cell Rep. 2014; 2: 406-413Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, paper, the amount of resected myocardium by ventricular weight 2 days after resection was in excess of 40%. We have not examined the effect of resection of such a large segment of the myocardium, but it is plausible that it is not compatible with regeneration. We stand by the reproducibility of the initial report and we would be happy to assist Andersen et al., 2014Andersen D.C. Ganesalingam S. Jensen C.H. Sheikh S.P. Stem Cell Rep. 2014; 2: 406-413Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar with various technical aspects of the neonatal apical resection method. All authors contributed equally to this letter. Do Neonatal Mouse Hearts Regenerate following Heart Apex Resection?Andersen et al.Stem Cell ReportsApril 08, 2014In BriefNeonatal mouse hearts have been reported to be regenerative following apex resection. However, in this study, Andersen, Sheikh, and colleagues were unable to reproduce this. Specifically, they found that the resected apex remains lost, cardiomyocyte proliferation is reduced, and that the wounded heart heals by a scarring response similar to that observed in the inert adult heart following damage. Full-Text PDF Open AccessMulti-Investigator Letter on Reproducibility of Neonatal Heart Regeneration following Apical ResectionSadek et al.Stem Cell ReportsOctober 14, 2014In Brief(Stem Cell Reports 3, 1, July 8, 2014) Full-Text PDF Open AccessResponse to Sadek et al. and Kotlikoff et al.Andersen et al.Stem Cell ReportsJuly 08, 2014In BriefIn our recent publication in Stem Cell Reports (Andersen et al., 2014), we resected neonatal mouse hearts and examined their ability to regenerate. As described previously (Porrello et al., 2011), we found that all hearts healed but, unexpectedly, this was accompanied with profound scarring of the apex, much like in damaged adult hearts, and little neomyogenesis. In their letter to the editor, Kotlikoff et al., 2014, emphasize the importance of distinguishing between regeneration and neomyogenesis. Full-Text PDF Open Access