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Heart to heart: grafting cardiosphere-derived cells augments cardiac self-repair by both myocytes and stem cells.

Palacios JA, Schneider MD - EMBO Mol Med (2013)

View Article: PubMed Central - PubMed

Affiliation: British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Imperial College London, London, UK.

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→See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201201737 Compared with highly regenerative organisms such as newts and zebrafish (Kikuchi & Poss, ), the capacity of mammalian adult heart tissue to undergo self-repair is insufficient to reconstitute the muscle lost in myocardial infarction, hindering functional recovery from heart attacks and from cell loss occurring in chronic heart failure (Mercola et al, )... However, overriding or inactivating tumour suppressor pocket proteins is one route to engineer persistent cycling in the adult heart (Mercola et al, ), and low levels of on-going myocyte generation have been demonstrated by fate-mapping in mice (Hsieh et al, ) and C dating in human heart tissue (Bergmann et al, )... Alternatively, the robust scarless healing of the heart in zebrafish occurs by differentiated myocytes re-entering the cell cycle (Kikuchi & Poss, ), a mechanism that is available to mice only during the first days of life (Porrello et al, )... Moreover, the quantitative replacement of GFP by LacZ-expressing myocytes excludes factitious dilution of the starting myocytes, as might occur by reductions in transgene expression via DNA methylation and transcriptional silencing... An equally exciting discovery made using this system was the evidence that the beneficial effect of c-kit bone marrow cells on the injured mouse heart involved myocyte generation by the activation of endogenous cardiac progenitor or stem cells (Loffredo et al, )... This effect was not seen with bone marrow mesenchymal stem cells, excluding a non-descript or generic effect of cell delivery and raising the possibility that other cell types might be even more active. »…these findings suggest a contribution to new myocyte formation following infarction both from pre-existing myocytes and from undifferentiated precursor cells« In this issue of EMBO Molecular Medicine, Malliaras and colleagues have applied this lineage tracing system, together with other tools, to address the thematically related question of how heart-derived cells benefit the heart (Malliaras et al, )... Few grafted cells survived beyond the first three weeks, signifying that the observed benefits in cardiomyocyte number, cardiac geometry, and cardiac pump function should be ascribed to enhancing self-repair, not an enduring role of the grafted cells themselves... Differences from earlier fate-mapping studies that failed to detect a similar contribution by preformed cardiomyocytes (Hsieh et al, ; Loffredo et al, ) were viewed as likely arising from the greater sensitivity here, using dissociated cells plus longer BrdU pulses... An intriguing article in Nature by the group that pioneered fate-mapping in cardiac self-repair (Hsieh et al, ; Loffredo et al, ) has re-examined this vexing question about the cellular origin of newly formed cardiomyocytes after myocardial infarction (Senyo et al, )... The combination of these two pulse-chase techniques—GFP fluorescence and N/N ratiometric imaging—allowed the researchers to compare the extent of DNA replication after injury in cardiomyocytes derived from pre-existing ones versus cardiomyocytes derived from undifferentiated precursors... With this change in methodology, Senyo and colleagues drew conclusions contrasting with their previously reported results: the prevalence of N labelling did not differ significantly between GFP and GFP myocytes, suggesting that dilution of the GFP cardiomyocyte pool cannot be explained by expansion and differentiation of endogenous stem or progenitor cells... The intriguing discrepancy concerns whether undifferentiated cardiac precursors contribute to the formation of new heart muscle after injury... Why these discordant results?

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Cardiosphere-derived cells stimulate the formation of new cardiomyocytes following infarction both from preformed cardiomyocytes and from undifferentiated progenitor or stem cellsDonor cells did not stably engraft, yet conferred an improvement in cardiac structure and pump function. Fate-mapping with the Cre/lox system ascribed new cardiomyocyte creation both to proliferation of pre-existing myocytes and to the differentiation of formerly undifferentiated cells.
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fig01: Cardiosphere-derived cells stimulate the formation of new cardiomyocytes following infarction both from preformed cardiomyocytes and from undifferentiated progenitor or stem cellsDonor cells did not stably engraft, yet conferred an improvement in cardiac structure and pump function. Fate-mapping with the Cre/lox system ascribed new cardiomyocyte creation both to proliferation of pre-existing myocytes and to the differentiation of formerly undifferentiated cells.

Mentions: In this issue of EMBO Molecular Medicine, Malliaras and colleagues have applied this lineage tracing system, together with other tools, to address the thematically related question of how heart-derived cells benefit the heart (Malliaras et al, 2013). Using mouse cardiosphere-derived cells that correspond to the human cells tested in CADUCEUS (Makkar et al, 2012), one striking effect of cell grafting was an increase in cycling of pre-existing myocytes, as measured by Ki67, BrdU incorporation into DNA, and histone H3 phospho-epitope staining, which denotes Cdc2 activity in mitosis. Cycling myocytes tended to be small, mono-nucleated, and adjacent to the area of injury. In addition, the authors notably observed the dilution of GFP+ myocytes by GFP− ones, and an even larger increase in cycling of this GFP− cardiomyocyte population. Together, these findings suggest a contribution to new myocyte formation following infarction both from pre-existing myocytes and from undifferentiated precursor cells, with enhancement of both regenerative pathways by cell grafting (Fig 1). Numerous precautions were undertaken to exclude alternative explanations like DNA synthesis without karyokinesis and cytokinesis. For instance, roughly 10% of the BrdU+ cardiomyocyte nuclei were more than diploid, but this small fraction would not account for the observed extent of cell cycle activity. Few grafted cells survived beyond the first three weeks, signifying that the observed benefits in cardiomyocyte number, cardiac geometry, and cardiac pump function should be ascribed to enhancing self-repair, not an enduring role of the grafted cells themselves. Differences from earlier fate-mapping studies that failed to detect a similar contribution by preformed cardiomyocytes (Hsieh et al, 2007; Loffredo et al, 2011) were viewed as likely arising from the greater sensitivity here, using dissociated cells plus longer BrdU pulses. In addition, paracrine differences between heart-derived cells and bone marrow cells cannot be excluded as a basis for different outcomes between the modes of cell therapy tested.


Heart to heart: grafting cardiosphere-derived cells augments cardiac self-repair by both myocytes and stem cells.

Palacios JA, Schneider MD - EMBO Mol Med (2013)

Cardiosphere-derived cells stimulate the formation of new cardiomyocytes following infarction both from preformed cardiomyocytes and from undifferentiated progenitor or stem cellsDonor cells did not stably engraft, yet conferred an improvement in cardiac structure and pump function. Fate-mapping with the Cre/lox system ascribed new cardiomyocyte creation both to proliferation of pre-existing myocytes and to the differentiation of formerly undifferentiated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569635&req=5

fig01: Cardiosphere-derived cells stimulate the formation of new cardiomyocytes following infarction both from preformed cardiomyocytes and from undifferentiated progenitor or stem cellsDonor cells did not stably engraft, yet conferred an improvement in cardiac structure and pump function. Fate-mapping with the Cre/lox system ascribed new cardiomyocyte creation both to proliferation of pre-existing myocytes and to the differentiation of formerly undifferentiated cells.
Mentions: In this issue of EMBO Molecular Medicine, Malliaras and colleagues have applied this lineage tracing system, together with other tools, to address the thematically related question of how heart-derived cells benefit the heart (Malliaras et al, 2013). Using mouse cardiosphere-derived cells that correspond to the human cells tested in CADUCEUS (Makkar et al, 2012), one striking effect of cell grafting was an increase in cycling of pre-existing myocytes, as measured by Ki67, BrdU incorporation into DNA, and histone H3 phospho-epitope staining, which denotes Cdc2 activity in mitosis. Cycling myocytes tended to be small, mono-nucleated, and adjacent to the area of injury. In addition, the authors notably observed the dilution of GFP+ myocytes by GFP− ones, and an even larger increase in cycling of this GFP− cardiomyocyte population. Together, these findings suggest a contribution to new myocyte formation following infarction both from pre-existing myocytes and from undifferentiated precursor cells, with enhancement of both regenerative pathways by cell grafting (Fig 1). Numerous precautions were undertaken to exclude alternative explanations like DNA synthesis without karyokinesis and cytokinesis. For instance, roughly 10% of the BrdU+ cardiomyocyte nuclei were more than diploid, but this small fraction would not account for the observed extent of cell cycle activity. Few grafted cells survived beyond the first three weeks, signifying that the observed benefits in cardiomyocyte number, cardiac geometry, and cardiac pump function should be ascribed to enhancing self-repair, not an enduring role of the grafted cells themselves. Differences from earlier fate-mapping studies that failed to detect a similar contribution by preformed cardiomyocytes (Hsieh et al, 2007; Loffredo et al, 2011) were viewed as likely arising from the greater sensitivity here, using dissociated cells plus longer BrdU pulses. In addition, paracrine differences between heart-derived cells and bone marrow cells cannot be excluded as a basis for different outcomes between the modes of cell therapy tested.

View Article: PubMed Central - PubMed

Affiliation: British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Imperial College London, London, UK.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

→See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201201737 Compared with highly regenerative organisms such as newts and zebrafish (Kikuchi & Poss, ), the capacity of mammalian adult heart tissue to undergo self-repair is insufficient to reconstitute the muscle lost in myocardial infarction, hindering functional recovery from heart attacks and from cell loss occurring in chronic heart failure (Mercola et al, )... However, overriding or inactivating tumour suppressor pocket proteins is one route to engineer persistent cycling in the adult heart (Mercola et al, ), and low levels of on-going myocyte generation have been demonstrated by fate-mapping in mice (Hsieh et al, ) and C dating in human heart tissue (Bergmann et al, )... Alternatively, the robust scarless healing of the heart in zebrafish occurs by differentiated myocytes re-entering the cell cycle (Kikuchi & Poss, ), a mechanism that is available to mice only during the first days of life (Porrello et al, )... Moreover, the quantitative replacement of GFP by LacZ-expressing myocytes excludes factitious dilution of the starting myocytes, as might occur by reductions in transgene expression via DNA methylation and transcriptional silencing... An equally exciting discovery made using this system was the evidence that the beneficial effect of c-kit bone marrow cells on the injured mouse heart involved myocyte generation by the activation of endogenous cardiac progenitor or stem cells (Loffredo et al, )... This effect was not seen with bone marrow mesenchymal stem cells, excluding a non-descript or generic effect of cell delivery and raising the possibility that other cell types might be even more active. »…these findings suggest a contribution to new myocyte formation following infarction both from pre-existing myocytes and from undifferentiated precursor cells« In this issue of EMBO Molecular Medicine, Malliaras and colleagues have applied this lineage tracing system, together with other tools, to address the thematically related question of how heart-derived cells benefit the heart (Malliaras et al, )... Few grafted cells survived beyond the first three weeks, signifying that the observed benefits in cardiomyocyte number, cardiac geometry, and cardiac pump function should be ascribed to enhancing self-repair, not an enduring role of the grafted cells themselves... Differences from earlier fate-mapping studies that failed to detect a similar contribution by preformed cardiomyocytes (Hsieh et al, ; Loffredo et al, ) were viewed as likely arising from the greater sensitivity here, using dissociated cells plus longer BrdU pulses... An intriguing article in Nature by the group that pioneered fate-mapping in cardiac self-repair (Hsieh et al, ; Loffredo et al, ) has re-examined this vexing question about the cellular origin of newly formed cardiomyocytes after myocardial infarction (Senyo et al, )... The combination of these two pulse-chase techniques—GFP fluorescence and N/N ratiometric imaging—allowed the researchers to compare the extent of DNA replication after injury in cardiomyocytes derived from pre-existing ones versus cardiomyocytes derived from undifferentiated precursors... With this change in methodology, Senyo and colleagues drew conclusions contrasting with their previously reported results: the prevalence of N labelling did not differ significantly between GFP and GFP myocytes, suggesting that dilution of the GFP cardiomyocyte pool cannot be explained by expansion and differentiation of endogenous stem or progenitor cells... The intriguing discrepancy concerns whether undifferentiated cardiac precursors contribute to the formation of new heart muscle after injury... Why these discordant results?

Show MeSH
Related in: MedlinePlus