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approaches, a secretome of soluble factors such as growth factors, exosomes, and miRNAs are thought
to be responsible for the beneficial effects [48-50] . The specific paracrine stimulation may vary by implanted
cell type and may be modulated by the cell culture environment, delivery platform, and other relevant
variables.

In pre-clinical studies Lancaster et al. [14-16,35] did not immune suppress their animals and long-term
physiologic benefits were seen when implanting human xenografts in immune-competent animals. The
transplanted PSC-CMs did not persist beyond four weeks post-implantation, but the initial functional
[35]
benefit continued to persist at ten weeks post-implantation .

SAFETY CONSIDERATIONS
The use of PSC-derived cells offer potential as a source for therapeutic advancements in all tissues, not
just the heart. The safety of these cell preparations when implanted in patients is obviously important. The
potential for tumorigenicity resulting from undifferentiated PSCs contaminants is a concern, particularly
with integrating cell preparations. The Food and Drug Administration requires extensive preclinical
testing for teratoma formation before approving PSC-derived preparations for clinical use. During somatic
skeletal myoblasts injections into the myocardium, ectopic foci were established that generated VT from
[9]
spontaneously depolarizing cells . The finding of increased incidence of ventricular tachyarrhythmia has
also been reported with human embryonic stem cell-derived cardiomyocyte injections into non-human
primates and swine hearts [51,52] . Interestingly in preclinical studies with PSC-CMs TE scaffolds implanted
on the epicardium, the animals remain in normal sinus rhythm without any arrhythmias [20,35] .

PROSPECTS FOR THE FUTURE
Looking into the future to predict the next advances of TE approaches to treat CHF is difficult but while
creating a cardiac patch has received a lot of interest, there are a number of other potential approaches.
Investigators have proposed decellularizing entire hearts and then repopulating with new PSC-derived
[54]
[53]
cells . There are also efforts to use 3-D printing to print entire organs . Synthesizing microvesicles such
as exosomes or secretomes that are secreted from the PSC-derived cells are being explored as a way to
[48]
bypass cell-based therapy and still retain the paracrine effect . Some of the issues outlined previously
need to be addressed such as the best strategies for immune suppression in patients, required maturity
of PSC-derived cells, use of integrating or non-integrating approaches and duration of transplanted cell
survival in order to result in the most beneficial effects. A recent review summarizes the “bottlenecks” for
[55]
the future of TE cardiac scaffolds . Despite these issues, we see a bright future for using TE approaches for
regenerative cardiology and all of medicine. The FDA now has a rapid approval process for cell therapy and
therapeutic TE products. The Regenerative Medicine Advanced Therapy designation of the 21st Century
Cures Act is designed to help accelerate medical product development and bring new innovations and
[56]
advancements to the patients who need them urgently .

CONCLUSIONS
The availability of PSC-derived cells and ability to generate TE approaches have introduced a unique
opportunity to develop novel strategies to treat patients. While there remain points of concern that need
to be addressed with respect to PSC-derived therapy, such as defining the mechanisms of action and the
potential need for immune suppression the field as a whole is moving forward and TE surgical therapies
for regenerative cardiology are closer to reality today than ever before.