The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived C-14 revealed a high turnover rate of endothelial cells throughout life (>15% per year) and more limited renewal of mesenchymal cells (<4% per year in adulthood). Cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood, with similar turnover rates in the major subdivisions of the myocardium. We provide an integrated model of cell generation and turnover in the human heart.

It has been unclear whether ischemic stroke induces neurogenesis or neuronal DNA rearrangements in the human neocortex. Using immunohistochemistry; transcriptome, genome and ploidy analyses; and determination of nuclear bomb test-derived (14)C concentration in neuronal DNA, we found neither to be the case. A large proportion of cortical neurons displayed DNA fragmentation and DNA repair a short time after stroke, whereas neurons at chronic stages after stroke showed DNA integrity, demonstrating the relevance of an intact genome for survival.

The myelination of axons by oligodendrocytes has been suggested to be modulated by experience, which could mediate neural plasticity by optimizing the performance of the circuitry. We have assessed the dynamics of oligodendrocyte generation and myelination in the human brain. The number of oligodendrocytes in the corpus callosum is established in childhood and remains stable after that. Analysis of the integration of nuclear bomb test-derived (14)C revealed that myelin is exchanged at a high rate, whereas the oligodendrocyte population in white matter is remarkably stable in humans, with an annual exchange of 1/300 oligodendrocytes. We conclude that oligodendrocyte turnover contributes minimally to myelin modulation in human white matter and that this instead may be carried out by mature oligodendrocytes, which may facilitate rapid neural plasticity.

Central nervous system injuries are accompanied by scar formation. It has been difficult to delineate the precise role of the scar, as it is made by several different cell types, which may limit the damage but also inhibit axonal regrowth. We show that scarring by neural stem cell-derived astrocytes is required to restrict secondary enlargement of the lesion and further axonal loss after spinal cord injury. Moreover, neural stem cell progeny exerts a neurotrophic effect required for survival of neurons adjacent to the lesion. One distinct component of the glial scar, deriving from resident neural stem cells, is required for maintaining the integrity of the injured spinal cord.

HomeCirculation ResearchVol. 110, No. 1Cardiomyocyte Renewal in Humans Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBCardiomyocyte Renewal in Humans Olaf Bergmann, Sofia Zdunek, Jonas Frisén, Samuel Bernard, Henrik Druid and Stefan Jovinge Olaf BergmannOlaf Bergmann Search for more papers by this author , Sofia ZdunekSofia Zdunek Search for more papers by this author , Jonas FrisénJonas Frisén Search for more papers by this author , Samuel BernardSamuel Bernard Search for more papers by this author , Henrik DruidHenrik Druid Search for more papers by this author and Stefan JovingeStefan Jovinge Search for more papers by this author Originally published6 Jan 2012https://doi.org/10.1161/CIRCRESAHA.111.259598Circulation Research. 2012;110:e17–e18To the Editor:In a recent review article by Leri, Kajstura, and Anversa1 in Circulation Research, there are several misrepresentations and factual errors in the description of our study on birth dating of heart cells.2 These errors affect their conclusions, and it is thus important to make some clarifications.First, Leri et al1 claim that we analyzed 12 pathological hearts, which is incorrect. Briefly, only 1 of the 12 studied subjects had a history of cardiac disease (a previous myocardial infarction) and was the only individual who had heart enlargement or any medication for cardiovascular disease (nitrates). Another individual died of acute myocardial infarction and displayed myocardial hypertrophy and moderate coronary sclerosis at autopsy. Of the remaining 10 individuals, 4 had slight myocardial hypertrophy, slight coronary sclerosis, and/or slight fibrosis detected at autopsy, and 1 of these had hypertension. The remaining 6 of the 12 studied individuals had neither a history of cardiovascular disease nor any sign of cardiac pathology at autopsy. Detailed information, including all of the above, was provided in our original study (Table S2), and we addressed the potential role of cardiac pathology in some of the included cases in our original publication.2Second, Leri et al1 claim that we assessed the birth date of a subpopulation of cardiomyocytes based on their suggestion that cardiac troponin I (cTnI) is localized in the nucleus only in a senescent subset of cardiomyocytes.6 We have addressed their claim in a separate study,3 which they fail to mention. We could not reproduce their finding using the conditions they describe in their study6 or using a range of other conditions.3 More importantly, and regardless of whether there may be a condition where one can distinguish different amounts of nuclear cTnI in cardiomyocytes, we have provided extensive characterization of the population we analyzed, which rules out that their suggestion is valid for our analysis.2,3 We identified 36.2±8.5% (mean±SD) of myocardial nuclei as cardiomyocyte nuclei, and there was no increase in the proportion of positive nuclei with age.3 This corresponds well to what one would expect if all cardiomyocyte nuclei were labeled, given that cardiomyocytes constitute 20% to 40% of the cells in the myocardium, and 25% of them are binucleated.4,5 Close to all RNA encoding the cardiomyocyte markers cTnT, cTnI, Nkx2.5, and Gata-4 is found in the cardiac troponin–positive nuclear population. Already this excludes their suggestion that we have missed a population with cytoplasmic but not nuclear cTnI, because we isolated almost all nuclei with cTnI RNA. Moreover, we independently isolated cardiomyocyte nuclei with antibodies to cTnT, which had 14C concentrations corroborating the data obtained by isolating cardiomyocyte nuclei with cTnI.2 We also demonstrated that cardiomyocytes sorted on the basis of the presence of cytoplasmic myosin heavy chain have cTnI- and cTnT-positive nuclei.2 We further established pericentriolar material 1 (PCM-1) as an additional marker to identify and isolate cardiomyocyte nuclei.3 PCM-1–positive nuclei showed an almost complete overlap with cardiac troponin–positive nuclei,3 documenting again that virtually all cardiomyocytes were 14C dated in our study.2 Thus, as we have reported previously,2,3 our findings are incompatible with their suggestion that we select for nuclei of a subpopulation of cTnI-expressing cells with a particular subcellular distribution of the protein.Third, Leri et al1 question our interpretation of the 14C data. We used a mathematical model that is suitable for estimating cell turnover, both in slowly and fast dividing cell populations.7 This model is not limited to the assumption of a constant cell number and therefore is appropriate when analyzing tissues with a changing cell number.8 We developed 12 different scenarios for turnover based on the mathematical model, of which 2 (A and B) assumed constant renewal rates, and only 1 (A) assumed constant renewal rates and cell number. Four of 12 tested scenarios allowed the cell number and turnover rate to vary. However, this did not improve the overall fitting of the data. Leri et al1 falsely claim that we have grouped the subjects according to birth before and after the period of nuclear bomb tests. There was no grouping, and the model treats young and old subjects in the exact same way. It is, however, important to understand that 14C levels must be interpreted differently in young and old: For subjects born before 1955, 14C levels above those at the time of birth of the individual are indicative of turnover, whereas for subjects born after 1963, it is 14C levels below those at the time of birth that are indicative of cell turnover. For subjects born between 1955 and 1963 during the rapid increase in 14C levels, cell turnover can both elevate and depress 14C levels in DNA. This is accounted for in the model. Nevertheless, Leri et al1 imply that our model was erroneous because some estimated noncardiomyocyte 14C concentrations were lower than the atmospheric 14C concentrations. We agree, as stated in our initial publication, that nonmyocyte turnover estimates determined indirectly are not as robust as the cardiomyocyte turnover rate, and this will be important to address further in future studies. However, the noncardiomyocyte estimate of 14C concentrations shown in the article by Leri et al1 (Figure 8F, right panel) is incorrect. The noncardiomyocyte estimate should have a Δ14C value of 42.76 (case ND51; see Bergmann et al2), which is above the prebomb atmospheric 14C concentration and incompatible with a 14C level of a cell population born 1000 AD.The finding that human cardiomyocytes can be replaced throughout adulthood represents a paradigm shift in cardiovascular biology. Careful data interpretation and an appropriate mathematical analysis are required to characterize this process.Olaf BergmannSofia ZdunekJonas Frisén Department of Cell and Molecular Biology Karolinska Institute Stockholm, SwedenSamuel Bernard CNRS UMR5208 Institut Camille Jordan Université Claude Bernard Lyon 1 Villeurbanne, FranceHenrik Druid Department of Forensic Medicine Karolinska Institute Stockholm, SwedenStefan Jovinge Lund Strategic Research Center for Stem Cell Biology and Cell Therapy Department of Cardiology Lund University Hospital Lund, SwedenDisclosuresNone.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.This letter was handled by James Willerson, Consulting Editor. References 1. Leri A, Kajstura J, Anversa P. Role of cardiac stem cells in cardiac pathophysiology: a paradigm shift in human myocardial biology. Circ Res. 2011; 109: 941–961.LinkGoogle Scholar2. Bergmann O, Bhardwaj R, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz B, Druid H, Jovinge S, Frisen J. Evidence for cardiomyocyte renewal in humans. Science. 2009; 324: 98–102.CrossrefMedlineGoogle Scholar3. Bergmann O, Zdunek S, Alkass K, Druid H, Bernard S, Frisén J. Identification of cardiomyocyte nuclei and assessment of ploidy for the analysis of cell turnover. Exp Cell Res. 2011; 327: 188–194.CrossrefGoogle Scholar4. Olivetti G, Cigola E, Maestri R, Corradi D, Lagrasta C, Gambert SR, Anversa P. Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart. J Mol Cell Cardiol. 1996; 28: 1463–1477.CrossrefMedlineGoogle Scholar5. Rubart M, Field LJ. Cardiac regeneration: repopulating the heart. Annu Rev Physiol. 2006; 68: 29–49.CrossrefMedlineGoogle Scholar6. Kajstura J, Urbanek K, Perl S, Hosoda T, Zheng H, Ogorek B, Ferreira-Martins J, Goichberg P, Rondon-Clavo C, Sanada F, D'Amario D, Rota M, Del Monte F, Orlic D, Tisdale J, Leri A, Anversa P. Cardiomyogenesis in the adult human heart. Circ Res. 2010; 107: 305–315.LinkGoogle Scholar7. Bernard S, Frisén J, Spalding KL. A mathematical model for the interpretation of nuclear bomb test derived 14C incorporation in biological systems. Nucl Instrum Methods Phys Res B. 2010; 268: 1295–1298.CrossrefGoogle Scholar8. Spalding K, Arner E, Westermark P, Bernard S, Buchholz B, Bergmann O, Blomqvist L, Hoffstedt J, Näslund E, Britton T, Concha H, Hassan M, Rydén M, Frisén J, Arner P. Dynamics of fat cell turnover in humans. 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January 6, 2012Vol 110, Issue 1 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.111.259598PMID: 22223215 Originally publishedJanuary 6, 2012 PDF download Advertisement SubjectsDevelopmental BiologyMyocardial Regeneration

We and other groups have reported cardiomyocyte renewal in adult human hearts. However, there is no consensus about magnitude and regional heterogeneity in myocardial turnover. Important requirements to quantify cellular turnover are the accurate identification of cardiomyocytes and ploidy level. We present a regional analysis of turnover in the adult myocardium, using the integration of atmospheric radiocarbon (14C) into genomic myocardial DNA. Cardiomyocyte nuclei were labeled with pericentriolar protein 1 (PCM-1) and isolated by flow cytometry. In order to improve estimates on cardiomyocyte turnover, nuclei were isolated according to their DNA content. A substantial fraction of cardiomyocyte nuclei in the right and left ventricle were polyploid: 28.9%±10.6% diploid, 58.9%±8.5% tetraploid and 12.1%±7.4% octaploid in the left ventricle and 47.9%±10.6% diploid, 46.6%±8.3% tetraploid and 5.6%±3.2% octaploid in the right ventricle. Cardiomyocyte turnover was analyzed according to their ploidy distribution in the left and right ventricle. Data from this ongoing study indicates a limited regenerative potential in both ventricles. A comprehensive mathematical analysis of regional turnover distribution will be presented. Non-cardiomyocytes were in average 18.0±2.3 years younger than the respective subjects, indicating a substantial turnover in the whole myocardium. The human heart has the capability to regenerate cardiomyocytes. However, the magnitude of this process does not allow for the renewal of the whole myocardium under homeostatic condition in a lifetime. Understanding the underlying mechanisms of cardiac renewal will open up new avenues to treat cardiac injuries.

Assays to quantify myocardial renewal rely on the accurate identification of cardiomyocyte nuclei. We previously ¹⁴C birth dated human cardiomyocytes based on the nuclear localization of cTroponins T and I. A recent report by Kajstura et al. suggested that cTroponin I is only localized to the nucleus in a senescent subpopulation of cardiomyocytes, implying that ¹⁴C birth dating of cTroponin T and I positive cell populations underestimates cardiomyocyte renewal in humans. We show here that the isolation of cell nuclei from the heart by flow cytometry with antibodies against cardiac Troponins T and I, as well as pericentriolar material 1 (PCM-1), allows for isolation of close to all cardiomyocyte nuclei, based on ploidy and marker expression. We also present a reassessment of cardiomyocyte ploidy, which has important implications for the analysis of cell turnover, and iododeoxyuridine (IdU) incorporation data. These data provide the foundation for reliable analysis of cardiomyocyte turnover in humans.

Signaling proteins driving the proliferation of stem and progenitor cells are often encoded by proto-oncogenes. EphB receptors represent a rare exception; they promote cell proliferation in the intestinal epithelium and function as tumor suppressors by controlling cell migration and inhibiting invasive growth. We show that cell migration and proliferation are controlled independently by the receptor EphB2. EphB2 regulated cell positioning is kinase-independent and mediated via phosphatidylinositol 3-kinase, whereas EphB2 tyrosine kinase activity regulates cell proliferation through an Abl-cyclin D1 pathway. Cyclin D1 regulation becomes uncoupled from EphB signaling during the progression from adenoma to colon carcinoma in humans, allowing continued proliferation with invasive growth. The dissociation of EphB2 signaling pathways enables the selective inhibition of the mitogenic effect without affecting the tumor suppressor function and identifies a pharmacological strategy to suppress adenoma growth.

It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.