- Scientists develop a radically new approach to
grow adult-like human heart muscle from human induced pluripotent (capable of
giving rise to many tissues, for example heart muscle, liver, skin, nerve) stem
cells (iPSCs), in just four weeks of bio-reactor cultivation.
- The lesser time taken,
and the more mature adult-like heart muscle produced would make it faster,
cheaper and better to study heart muscle function and
- Current methods to engineer heart muscle in the
lab takes around nine months and the heart tissue produced is not as mature,
limiting their use in biomedical research.
and radical approach to create human
adult-like heart muscle from human induced pluripotent stem cells could be a
in future biomedical research, according to a team of
scientists at Columbia Engineering. The findings of their study appear in the
Reason for Study
huge advances in the field of biomedical engineering and stem
research, current bioengineered tissues do not live upto
expectations and fail to show essential features of adult human heart function.
As a result,
the currently lab-cultivated heart muscle is not mature enough for research
current study team hoped to overcome this critical barrier
design heart muscle,
as close to native heart muscle as possible, that would open up opportunities for biomedical research.
‘Creating human like mature heart muscle in the lab would help understand human physiology better, as well as predict the effects of disease or drugs on the native heart tissue.’
current efforts have been limited in how much maturation can be achieved, we
decided to try something totally new: to explore the concept of accelerated
development. It took a lot of creative thinking and clever engineering by the
whole team across both campuses of Columbia University to develop the model we
now have, a highly matured, patient-specific heart muscle that can be used for
studies of heart development, physiology, disease, and responses to
Details of Study
- They first induced human pluripotent stem cells from blood
which would then give rise to
early-stage cardiomyocytes (heart muscle). These early-stage
cardiomyocytes are able to beat spontaneously,
however are still flexible enough to be manipulated.
- These cardiomyocytes and the
supporting cells were then encapsulated
in a fibrin gelling solution to obtain an initial tissue template
around two elastic pillars.
- The team cultured the tissues in a
multi-chamber platform - an organ on a chip device consisting of several biological
replicates of small-size human heart muscle (measuring about 6 mm in
- The scientists applied electrical stimuli to force the bioengineered heart muscle
to twitch and work against the load (by pulling the elastic pillars),
precisely replicating what happens in healthy heart muscle in the human body.
- In addition to controlling the
environment by application of physical and molecular factors, the device
also enabled measurements of
numerous functional properties of heart muscle by measuring optical
- The team has
developed the methods and software
to measure the force, frequency, and amplitude of contractions, cell
signaling and propagation, and responses
New Concepts Tested Out
In Current Study
in our field has
been that the more mature the starting cardiomyocytes, the better,"
the study's lead author Kacey Ronaldson-Bouchard, then a graduate student and
now a postdoctoral scientist in Vunjak-Novakovic'sáLaboratory for Stem
Cells and Tissue Engineering.
- The team, however, found that
very early-stage cells, which were
still plastic enough to be manipulated during development, responded better to the external signals that drive
- The other major advance in this
study was that, instead of the
gentle mechanical stretch normally present in developing fetal heart, they applied a special regime of
"electromechanical conditioning", by gradually increasing the
frequency of electrically induced contractions day-by-day.
Results of the Special Electromechanical Conditioning Regime
- The above conditioning technique saw a rapid and unprecedented
maturation of the heart tissue structure, function and metabolism.
This method forced the cultured muscle to work harder each following day
compared to the previous day
just four weeks of culture, the tissues showed
adult-like gene expression profiles, remarkably organized ultrastructure,
and numerous functional properties seen in the mature human heart muscle.
resulting engineered tissue is truly unprecedented in its similarity to
functioning human tissue," said Seila Selimovic, director of the NIBIB
(National Institute of Biomedical Imaging and Bioengineering) Tissue Chips
program, within the National Institutes of Health that funded this research.
team has successfully managed to
compress the time
taken (four weeks against current nine
months) for early stage heart muscle to
mature into adult human like heart muscle by a special regime of conditioning
Applications of the
- The matured human heart muscle
produced, can be used to reproduce the features of some heart conditions, such
as the pathological hypertrophy of the heart or the decreased
contractility associated with certain conditions, for example calcium
- The team plans to extend the current
study into broader aspects of disease modeling to get a better
understanding of the mechanism of
cardiac disease and drug induced cardiotoxicity.
- The work could pave the way for discovery of new treatment targets
and lead to new cardioprotective or curative treatment options.
conclusion, engineered tissues that
closely resemble the adult human heart, can help predict better
effects of drugs or environmental factors on the actual heart tissue of a
patient. Such a human tissue model would help make drug development and other
research significantly faster, safer and cheaper.
- Kacey Ronaldson-Bouchard, Stephen P. Ma, Keith Yeager, Timothy Chen, LouJin Song, Dario Sirabella, Kumi
Morikawa, Diogo Teles, Masayuki Yazawa, Gordana Vunjak-Novakovic. "Advanced maturation of human cardiac tissue grown from pluripotent
stem cells". Nature, (2018); DOI: 10.1038/s41586-018-0016-3