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Regeneration of the heart.

Steinhauser ML, Lee RT - EMBO Mol Med (2011)

Bottom Line: First, although endogenous mammalian cardiac regeneration clearly seems to decline rapidly after birth, it may still persist in adulthood.Second, recent breakthroughs have enabled reprogramming of cells that were apparently terminally differentiated, either by dedifferentiation into pluripotent stem cells or by transdifferentiation into cardiac myocytes.In this review, we discuss the current status of research on cardiac regeneration, with a focus on the challenges that hold back therapeutic development.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Partners Research Building, Cambridge, MA, USA. msteinhauser@partners.org

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The majority of post-natal human DNA synthesis in the heart does not lead to new myocyte formationCardiac myocytes can complete S-phase, followed by mitosis and cytokinesis (centre) resulting in myocyte doubling. Cardiac myocytes can also complete mitosis without cytokinesis (left), resulting in a binucleated cell. Cardiac myocytes can also undergo chromosomal replication without completing either mitosis or cytokinesis (right), resulting in polyploidy nuclei. By the completion of post-natal development, the majority of human myocyte nuclei contain ≥4n chromosomal copies.
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fig01: The majority of post-natal human DNA synthesis in the heart does not lead to new myocyte formationCardiac myocytes can complete S-phase, followed by mitosis and cytokinesis (centre) resulting in myocyte doubling. Cardiac myocytes can also complete mitosis without cytokinesis (left), resulting in a binucleated cell. Cardiac myocytes can also undergo chromosomal replication without completing either mitosis or cytokinesis (right), resulting in polyploidy nuclei. By the completion of post-natal development, the majority of human myocyte nuclei contain ≥4n chromosomal copies.

Mentions: The heart also presents a unique challenge compared to other organs owing to the propensity of cardiac myocytes to synthesize DNA during S-phase without completing either mitosis and/or cytokinesis (Fig 1). During early post-natal development, for example, the majority of rodent cardiac myocytes (Li et al, 1996) and an estimated 25–57% of human cardiac myocytes (Olivetti et al, 1996; Schmid & Pfitzer, 1985) become binucleated. By adulthood, most cardiac myocyte nuclei have also become polyploid with at least one (4n: tetraploid) or two (8n: octoploid) additional rounds of chromosomal replication (Bergmann et al, 2010). Although some studies demonstrated that the polyploidy rate in the cardiac myocyte pool is not affected by ageing or injury (Olivetti et al, 1996), others suggested that the ploidy state is more dynamic. The ploidy state of cardiac myocytes may increase with myocardial hypertrophy or injury (Adler & Friedburg, 1986), which could be mistaken for myocyte division. Conversely, hearts that have been unloaded by implantation of a ventricular assist device may have a lower percentage of polyploid myocytes, because more 2n cardiac myocytes are being generated (Wohlschlaeger et al, 2010). These aspects of cardiac myocyte biology inevitably represent potential confounders that must be considered in any quantification of cardiac myocyte formation. As with any controversial hypothesis, achieving consensus regarding adult mammalian cardiac myocyte turnover will likely require multiple lines of evidence using multiple different methodologies.


Regeneration of the heart.

Steinhauser ML, Lee RT - EMBO Mol Med (2011)

The majority of post-natal human DNA synthesis in the heart does not lead to new myocyte formationCardiac myocytes can complete S-phase, followed by mitosis and cytokinesis (centre) resulting in myocyte doubling. Cardiac myocytes can also complete mitosis without cytokinesis (left), resulting in a binucleated cell. Cardiac myocytes can also undergo chromosomal replication without completing either mitosis or cytokinesis (right), resulting in polyploidy nuclei. By the completion of post-natal development, the majority of human myocyte nuclei contain ≥4n chromosomal copies.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3377117&req=5

fig01: The majority of post-natal human DNA synthesis in the heart does not lead to new myocyte formationCardiac myocytes can complete S-phase, followed by mitosis and cytokinesis (centre) resulting in myocyte doubling. Cardiac myocytes can also complete mitosis without cytokinesis (left), resulting in a binucleated cell. Cardiac myocytes can also undergo chromosomal replication without completing either mitosis or cytokinesis (right), resulting in polyploidy nuclei. By the completion of post-natal development, the majority of human myocyte nuclei contain ≥4n chromosomal copies.
Mentions: The heart also presents a unique challenge compared to other organs owing to the propensity of cardiac myocytes to synthesize DNA during S-phase without completing either mitosis and/or cytokinesis (Fig 1). During early post-natal development, for example, the majority of rodent cardiac myocytes (Li et al, 1996) and an estimated 25–57% of human cardiac myocytes (Olivetti et al, 1996; Schmid & Pfitzer, 1985) become binucleated. By adulthood, most cardiac myocyte nuclei have also become polyploid with at least one (4n: tetraploid) or two (8n: octoploid) additional rounds of chromosomal replication (Bergmann et al, 2010). Although some studies demonstrated that the polyploidy rate in the cardiac myocyte pool is not affected by ageing or injury (Olivetti et al, 1996), others suggested that the ploidy state is more dynamic. The ploidy state of cardiac myocytes may increase with myocardial hypertrophy or injury (Adler & Friedburg, 1986), which could be mistaken for myocyte division. Conversely, hearts that have been unloaded by implantation of a ventricular assist device may have a lower percentage of polyploid myocytes, because more 2n cardiac myocytes are being generated (Wohlschlaeger et al, 2010). These aspects of cardiac myocyte biology inevitably represent potential confounders that must be considered in any quantification of cardiac myocyte formation. As with any controversial hypothesis, achieving consensus regarding adult mammalian cardiac myocyte turnover will likely require multiple lines of evidence using multiple different methodologies.

Bottom Line: First, although endogenous mammalian cardiac regeneration clearly seems to decline rapidly after birth, it may still persist in adulthood.Second, recent breakthroughs have enabled reprogramming of cells that were apparently terminally differentiated, either by dedifferentiation into pluripotent stem cells or by transdifferentiation into cardiac myocytes.In this review, we discuss the current status of research on cardiac regeneration, with a focus on the challenges that hold back therapeutic development.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Partners Research Building, Cambridge, MA, USA. msteinhauser@partners.org

Show MeSH
Related in: MedlinePlus