CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 5, June 2013
AFRICA
189
Review Article
Can stem cells really regenerate the human heart?
Use your noggin, dickkopf!
Lessons from developmental biology
PAULA SOMMER
Abstract
The human heart is the first organ to develop and its develop-
ment is fairly well characterised. In theory, the heart has the
capacity to regenerate, as its cardiomyocytes may be capable
of cell division and the adult heart contains a cardiac stem cell
niche, presumably capable of differentiating into cardiomyo-
cytes and other cardiac-associated cell types. However, as with
most other organs, these mechanisms are not activated upon
serious injury. Several experimental options to induce regen-
eration of the damaged heart tissue are available: activate the
endogenous cardiomyocytes to divide, coax the endogenous
population of stem cells to divide and differentiate, or add
exogenous cell-based therapy to replace the lost cardiac tissue.
This review is a summary of the recent research into all these
avenues, discussing the reasons for the limited successes
of clinical trials using stem cells after cardiac injury and
explaining new advances in basic science. It concludes with a
reiteration that chances of successful regeneration would be
improved by understanding and implementing the basics of
heart development and stem cell biology.
Keywords:
heart development, stem cell clinical trials, iPS cells,
ES cells, paracrine signalling
Submitted 8/4/13, accepted 7/6/13
Cardiovasc J Afr
2013;
24
: 189–193
DOI: 10.5830/CVJA-2013-045
Development of the heart
Human development begins with the fertilisation of an ovum by
a sperm, initiating furious but intricately controlled cell division.
At implantation, the embryo is known as a blastocyst, consisting
of an outer trophoblast and an inner cell mass composed of
embryonic stem (ES) cells. These ES cells divide, move, respond
to cues from themselves and each other, and demonstrate
pluripotency, the ability to develop into all the tissues and organs
of the human body.
As the embryo develops into a foetus, the cells lose
pluripotency and progress towards a more differentiated state,
contributing to the formation of organs. Their potency therefore
becomes more and more restricted. Every organ and tissue in
the adult body retains a niche of stem cells whose potency is
generally specific to the cells of the resident tissue.
The heart is the first organ to form in the developing embryo.
The vertebrate heart develops from two regions of splanchnic
mesoderm, one on each side of the developing embryo, that
interact with the directly adjacent tissue, the anterior endoderm.
The presence of the anterior endoderm is essential for heart
development, and the interaction between these two tissues
results in the specification of cells destined to form the heart
– the cardiogenic mesoderm.
1
The presence of certain cardiac-
restricted transcription factors such as
Gata4
2
and
Nkx2-5
3
are
essential for restricting the mesoderm to a cardiac fate.
The anterior endoderm secretes factors such as bone
morphogenetic proteins (BMPs) and fibroblast growth factors
(FGFs). The
Bmp2
gene particularly plays a role as, in mice in
which the
Bmp2
gene has been knocked out (
Bmp2
-/-
mice), the
heart either does not develop or develops poorly.
4
This range of
different phenotypes suggests a degree of genetic redundancy,
where other BMPs compensate for the lack of
Bmp2
. Such
effects are also noted for the different FGFs.
Along with the positive signals initiating heart development,
inhibitory signals prevent the heart from forming where it
shouldn’t. The notochord, which serves to define the central axis
of the embryo, secretes the BMP inhibitors noggin and chordin,
preventing the heart from forming in the centre of the embryo.
The anterior endoderm secretes Wnt inhibitors such as cerebrus,
dickkopf and crescent, which prevent Wnts from binding to their
receptors. Therefore cardiac precursor cells are specified in the
places where BMPs (from the lateral mesoderm and endoderm)
and Wnt antagonists (from the anterior endoderm) coincide.
5
This simplified description of heart development serves to
show that there is no straightforward recipe for the development
of the human heart. There is, however, information that can be
exploited.
Key message:
Heart development is a complex process promoted
by positive signals such as BMPs and shaped by negative signals
such as the Wnt inhibitors, cerebrus and dickkopf, and the BMP
inhibitors, noggin and chordin.
Can the human heart be induced to regenerate
after injury?
An estimated 17 million people worldwide die annually from
cardiovascular disease, particularly heart attacks and strokes
(
/
School of Life Sciences, University of KwaZulu-Natal,
Durban, South Africa
PAULA SOMMER, PhD,
