RESEARCH ARTICLE
Extracellular matrix formation after transplantation of human
embryonic stem cell-derived cardiomyocytes
L. W. van Laake
•
E. G. van Donselaar
•
J. Monshouwer-Kloots
•
C. Schreurs
•
R. Passier
•
B. M. Humbel
•
P. A. Doevendans
•
A. Sonnenberg
•
A. J. Verkleij
•
Christine L. Mummery
Received: 8 August 2009 / Revised: 29 September 2009 / Accepted: 7 October 2009 / Published online: 22 October 2009
Ó The Author(s) 2009. This article is published with open access at Springerlink.com
Abstract Transplantation of human embryonic stem cell-
derived cardiomyocytes (hESC-CM) for cardiac regenera-
tion is hampered by the formation of fibrotic tissue around
the grafts, preventing electrophysiological coupling. Inves-
tigating this process, we found that: (1) beating hESC-CM in
vitro are embedded in collagens, laminin and fibronectin,
which they bind via appropriate integrins; (2) after trans-
plantation into the mouse heart, hESC-CM continue to
secrete collagen IV, XVIII and fibronectin; (3) integrin
expression on hESC-CM largely matches the matrix type
they encounter or secrete in vivo; (4) co-transplantation of
hESC-derived endothelial cells and/or cardiac progenitors
with hESC-CM results in the formation of functional cap-
illaries; and (5) transplanted hESC-CM survive and mature
in vivo for at least 24 weeks. These results form the basis of
future developments aiming to reduce the adverse fibrotic
reaction that currently complicates cell-based therapies for
cardiac disease, and to provide an additional clue towards
successful engraftment of cardiomyocytes by co-trans-
planting endothelial cells.
Keywords Stem cells Á Extracellular matrix Á
Cell transplantation Á Myocardial infarction Á Blood vessels
Introduction
Heart failure is one of the most prevalent causes of mor-
bidity and mortality worldwide and is most commonly due
to loss of cardiomyocytes after myocardial infarction (MI)
[1]. Until recently, loss of viable cardiomyocytes was
considered irreversible since the adult mammalian myo-
cardium lacks the ability to regenerate. However, with the
discovery of stem cells with the capacity to differentiate
into cardiomyocytes and other cardiac cells, it may be
possible to replenish the diseased heart with new myocar-
dium [2, 3]. Human embryonic stem cells (hESC) are one
source that holds promise in this respect, since they can
proliferate indefinitely in culture and differentiate into
cardiomyocytes with acceptable efficiencies [4–6], thus
providing a potential source of cells for both chronic and
acute applications. However, aside from their ethical sen-
sitivity, several scientific issues need to be addressed
before clinical application becomes feasible. Questions
have emerged from studies on the engraftment of
hESC-derived cardiomyocytes (hESC-CM) in uninjured,
infarcted, and arrhythmic hearts of experimental animals
[5, 7–11]. These issues concern primarily integration, sur-
vival, safety, immunogenicity and ability to contribute
to long-term contractile function. When hESC-CM were
transplanted into electrophysiologically silenced guinea pig
and swine hearts, they acted as biological pacemakers for
Electronic supplementary material The online version of this
article (doi:10.1007/s00018-009-0179-z) contains supplementary
material, which is available to authorized users.
L. W. van Laake Á P. A. Doevendans
Heart Lung Center Utrecht, Utrecht, The Netherlands
E. G. van Donselaar Á B. M. Humbel Á A. J. Verkleij
Cellular Architecture and Dynamics, Faculty of Sciences,
Utrecht University, Utrecht, The Netherlands
J. Monshouwer-Kloots Á C. Schreurs Á R. Passier Á
C. L. Mummery (&)
Department of Anatomy and Embryology, Leiden University
Medical Center, Postal zone: S-1-P, P.O. Box 9600,
2300 RC Leiden, The Netherlands
e-mail: c.l.mummery@lumc.nl
A. Sonnenberg
The Netherlands Cancer Institute, Amsterdam, The Netherlands
Cell. Mol. Life Sci. (2010) 67:277–290
DOI 10.1007/s00018-009-0179-z
Cellular and Molecular Life Sciences