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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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Proposed mechanisms of action for cell-based therapiesIn theory, exogenously delivered cells may directly differentiate into endothelial cells, smooth muscle cells and cardiac myocytes. They may also release paracrine factors which may result in non-regenerative effects, such as immunomodulation, angiogenesis or cardioprotection. Recent work from our laboratory suggests that a dominant mechanism achieved with bone marrow progenitor therapy may be via the activation of endogenous progenitor recruitment (Loffredo et al, 2011).
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fig05: Proposed mechanisms of action for cell-based therapiesIn theory, exogenously delivered cells may directly differentiate into endothelial cells, smooth muscle cells and cardiac myocytes. They may also release paracrine factors which may result in non-regenerative effects, such as immunomodulation, angiogenesis or cardioprotection. Recent work from our laboratory suggests that a dominant mechanism achieved with bone marrow progenitor therapy may be via the activation of endogenous progenitor recruitment (Loffredo et al, 2011).

Mentions: A more realistic short-term goal may be to exploit paracrine signalling to amplify the existent endogenous regenerative response. Recent cell transplantation experiments conducted in our laboratory, using an inducible cre-based genetic lineage mapping approach, tested the hypothesis that cell-based therapies might exert proregenerative effects via a paracrine mechanism (Loffredo et al, 2011) (Fig 5). Consistent with some prior studies (Balsam et al, 2004; Murry et al, 2004), we found no evidence for transdifferentiation of exogenously delivered bone marrow cells into cardiac myocytes. However, we did find increased generation of cardiac myocytes from endogenous progenitors in mice, which were administered c-kit+ bone marrow cells but not mesenchymal stem cells. This finding suggests paracrine signalling between exogenously delivered cells and endogenous resident progenitors. It provides a rationale for therapeutic interventions aimed at activating progenitors or recruiting them from their niche to the injury site (Steinhauser & Lee, 2009). One such approach involves the administration of the peptide thymosin β4, which appears to induce WT-1-expressing epicardial cells to differentiate into de novo cardiac myocytes (Smart et al, 2011). Interestingly, the WT-1+ cells do not appear to differentiate into cardiac myocytes in the adult mouse without being primed by thymosin β4, which suggests the involvement of a reprogramming mechanism.


Regeneration of the heart.

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

Proposed mechanisms of action for cell-based therapiesIn theory, exogenously delivered cells may directly differentiate into endothelial cells, smooth muscle cells and cardiac myocytes. They may also release paracrine factors which may result in non-regenerative effects, such as immunomodulation, angiogenesis or cardioprotection. Recent work from our laboratory suggests that a dominant mechanism achieved with bone marrow progenitor therapy may be via the activation of endogenous progenitor recruitment (Loffredo et al, 2011).
© Copyright Policy
Related In: Results  -  Collection

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

fig05: Proposed mechanisms of action for cell-based therapiesIn theory, exogenously delivered cells may directly differentiate into endothelial cells, smooth muscle cells and cardiac myocytes. They may also release paracrine factors which may result in non-regenerative effects, such as immunomodulation, angiogenesis or cardioprotection. Recent work from our laboratory suggests that a dominant mechanism achieved with bone marrow progenitor therapy may be via the activation of endogenous progenitor recruitment (Loffredo et al, 2011).
Mentions: A more realistic short-term goal may be to exploit paracrine signalling to amplify the existent endogenous regenerative response. Recent cell transplantation experiments conducted in our laboratory, using an inducible cre-based genetic lineage mapping approach, tested the hypothesis that cell-based therapies might exert proregenerative effects via a paracrine mechanism (Loffredo et al, 2011) (Fig 5). Consistent with some prior studies (Balsam et al, 2004; Murry et al, 2004), we found no evidence for transdifferentiation of exogenously delivered bone marrow cells into cardiac myocytes. However, we did find increased generation of cardiac myocytes from endogenous progenitors in mice, which were administered c-kit+ bone marrow cells but not mesenchymal stem cells. This finding suggests paracrine signalling between exogenously delivered cells and endogenous resident progenitors. It provides a rationale for therapeutic interventions aimed at activating progenitors or recruiting them from their niche to the injury site (Steinhauser & Lee, 2009). One such approach involves the administration of the peptide thymosin β4, which appears to induce WT-1-expressing epicardial cells to differentiate into de novo cardiac myocytes (Smart et al, 2011). Interestingly, the WT-1+ cells do not appear to differentiate into cardiac myocytes in the adult mouse without being primed by thymosin β4, which suggests the involvement of a reprogramming mechanism.

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