The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical implications of basic research

New Cells in Old Hearts

Pontus Bostrm, M.D., Ph.D., and Jonas Frisn, M.D., Ph.D.
Unlike salamanders and zebra fish, in which
large parts of the heart are readily regenerated
after injury, the mammalian myocardium has
limited regenerative capacity. The loss of cardiomyocytes after a myocardial infarction in humans
typically results in scar formation, loss of contractile capacity, and reduced cardiac function.
One can envisage two conceptually different therapeutic strategies to restore the human myocardium: transplantation of contractile cells, perhaps
derived from stem cells in cell culture, or promotion of a latent endogenous regenerative capacity
in the heart. Most efforts have been directed toward cell-transplantation strategies.1 Two recent
studies2,3 described the dynamics of cardiomyocyte renewal and identified ways to promote their
regeneration in the adult mouse heart, suggesting that stimulating endogenous cardiac-repair
mechanisms may be rational and realistic.

Several studies have demonstrated the continuous generation of cardiomyocytes in the adult
mammalian heart, but the estimates of the extent of this process have varied substantially, and
it has been unclear whether these new cells derive from resident cardiac stem or progenitor cells
or from proliferating cardiomyocytes. Senyo and
colleagues2 used very sophisticated technology
to establish the renewal rate and origin of cardiomyocytes in adult mice. By detecting the nonradioactive stable nitrogen isotope 15N in the
DNA of cells undergoing mitosis by means of
mass spectrometry in tissue sections, they concluded that 0.8% of cardiomyocytes are replaced
annually in young adult mice and that this rate
of replacement declines during aging.2 This corresponds closely to estimates of the turnover dynamics in the human heart.4 By combining the
cell-proliferation analysis with genetic fate map-

Genetically labeled
cardiomyocyte

Aging
Nucleus of
new cell

Infarct
Ischemia
Unlabeled
noncardiomyocytes

Figure 1. Cardiomyocyte Division.

Senyo and colleagues2 introduced a stable and heritable genetic marker specifically in cardiomyocytes in the adult mouse heart and
simultaneously assessed mitotic cell division by means of incorporation of a labeled DNA building block (new cells are shown with red
nuclei). They established that new cardiomyocytes carry the cardiomyocyte
lineage marker and thus derive from proliferating cardiomyoC OLOR FIGURE
Draft 2of cardiomyocytes
3/13/2013
cytes during normal aging. They also found that the generation
increased after myocardial ischemia in mice, mainly
Frisen
Author
through increased cardiomyocyte proliferation but potentially
also
through
nonmitotic
differentiation of progenitor cells.
1
Fig #

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Title
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New Cells in Old Hearts

Phimister
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Clinical Implications of Basic Research

ping (a method used to determine the cellular

derivatives of a cell or population of cells) in
transgenic mice, Senyo and colleagues found
that most, if not all, new cells derive from dividing cardiomyocytes rather than from stem or progenitor cells in the normal adult heart (Fig. 1).
They also found that the rate of proliferation of
cardiomyocytes is elevated at the border of the
site of induced myocardial infarction in mice.
There was no indication of proliferating stem or
progenitor cells giving rise to new cardiomyocytes, although the authors propose that some
of the new cells generated after ischemia may
derive from progenitors differentiating into cardiomyocytes without proliferation.
The demonstration of cardiomyocyte proliferation prompts questions about how it is regulated and whether it can be modulated to promote
cardiac regeneration. MicroRNAs (miRNAs), short
RNA molecules blocking transcription or translation of specific target genes, are known to have
a strong effect on the heart, because complete
ablation of their function disrupts cardiac development and results in early postnatal death.5
Eulalio and colleagues3 performed a large-scale
screen for miRNAs that could specifically enhance the proliferation of neonatal rodent cardiomyocytes in vitro, and they identified a surprisingly large number of miRNAs that could
independently trigger cardiomyocyte mitosis.
Several of these miRNAs increased cardiomyocyte proliferation not only in adult cells in cell
culture but also in vivo when injected into the
heart or expressed by means of viral vectors in
mice (Fig. 2). Finally, Eulalio et al. showed that
forced independent expression of two miRNAs
resulted in robust cardiomyocyte regeneration
and improvement of cardiac function in a mouse
model of cardiac ischemia.
There are several challenges to the translation
of these new findings into cardiac regenerative
therapies. It will be important to establish
whether the features of cardiomyocyte generation
in pathologic situations in humans correspond to
those now established in mice. A better mechanistic understanding of how the specific miRNAs
exert their effects on the heart, especially in vivo,
is needed. Delivery of miRNAs is a challenge,
and effective delivery strategies that can be applied in the clinical situation have been elusive.
Moreover, unless strictly local administration is
possible, it will be important to assess the po-

n engl j med 368;14

Cardiomyocytes

High-throughput
screening identifies
specific microRNA that miRNAs
triggers cardiomyocyte
division

Cardiomyocytes
dividing

Mouse
heart

Infarct

Figure 2. Heart Mending with MicroRNAs (miRNAs).

Eulalio and colleagues3 performed a cell-culture screen
COLORthe
FIGURE
for miRNAs that promote
proliferation of rodent
Draft 2
3/13/2013
cardiomyocytes. Two
of the identified
miRNAs were
Bostrom/Frisen_cibr1300157
Author
delivered to the
heart2 in mice after myocardial ischeFig #
mia, resultingTitle
in an increase
New Cells in in
Old new
Hearts cardiomyocytes
and improvedDEcardiacPhimister
function.
ME
Artist
Pub Date

Laurencot
Williams
4/4/2013

AUTHOR PLEASE NOTE:

Figure has been redrawn and type has been reset

Please check carefully

tential side effects of specific miRNAs in other

organs. Nonetheless, these two studies, together with several other recent findings, show
that endogenous repair of the injured heart is
possible.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Department of Cell and Molecular Biology, Karolinska
Institute, Stockholm.

nejm.org

april 4, 2013

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clinical implications of basic research

1. Rosenzweig A. Cardiac regeneration. Science 2012;338:1549-

4. Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for

2. Senyo SE, Steinhauser ML, Pizzimenti CL, et al. Mammalian

5. Chen JF, Murchison EP, Tang R, et al. Targeted deletion of

50.

heart renewal by pre-existing cardiomyocytes. Nature 2013;493:

433-6.
3. Eulalio A, Mano M, Dal Ferro M, et al. Functional screening
identifies miRNAs inducing cardiac regeneration. Nature 2012;
492:376-81.

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cardiomyocyte renewal in humans. Science 2009;324:98-102.

Dicer in the heart leads to dilated cardiomyopathy and heart

failure. Proc Natl Acad Sci U S A 2008;105:2111-6.

DOI: 10.1056/NEJMcibr1300157
Copyright 2013 Massachusetts Medical Society.

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The New England Journal of Medicine

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Copyright 2013 Massachusetts Medical Society. All rights reserved.