Page 332 - Read Online

Lancaster et al. Vessel Plus 2019;3:34 I http://dx.doi.org/10.20517/2574-1209.2019.16 Page 3 of 8
[28]
immunosuppression . Gene editing may prove valuable in the future to generate cell therapy candidates
that integrate or persist in the host without losing potency.

ENGINEERED TISSUE TO TREAT HEART FAILURE
The development of cell-based TE approaches is exciting and in essence has the potential to generate a
[13]
therapeutic tissue with properties and function of the myocardium . Investigators have constructed
tissue patches that could be manipulated with respect to anisotropic components, degree of electrical
conductance, and mechanical qualities such as cardiomyocyte alignment and electromechanical coupling
or using decellularized starting material as a substrate [29,30] . Cardiac patches have been engineered with
nanotopographically-defined hydrogels meant to enhance cardiac regeneration by providing functional
[31]
cell-material interfaces . Three-dimensional (3-D) printing has also been utilized to generate TE scaffolds
by organizing special patterning of stem cells. The 3-D generated patches proved sufficient to promote rapid
vascularization with the potential to improve cardiac function and reverse maladaptive left ventricular
(LV) remodeling . Cardiac scaffolds have been made from electro-conductive acid-modified silk fibroin-
[32]
poly (pyrrole) substrates. With PSC derived cardiomyocytes these grafts showed enhanced gap junction
distribution and cardiomyocyte maturation [33,34] .

Lancaster et al. have developed a TE cardiac patch composed of a bioabsorbable scaffold embedded
[35]
with human neonatal fibroblasts and PSC-CMs that is implanted on the epicardial surface of the heart
to treat CHF. The fibroblasts proliferate and synthesize glycosaminoglycans, collagen, elastin, fibronectin
and laminin while providing a secretome of growth factors and cytokines. The fibroblasts support
the incorporation of the cardiomyocytes into the scaffold and the cardiomyocytes provide additional
complementary secretomes. This cardiac patch increases myocardial blood flow, reverses maladaptive
LV remodeling, activates endogenous growth factor secretion, recovers hibernating myocardium and
improves LV function and improves electrical propagation through the previously scarred myocardium
and enhances electrical stability of the healthy tissue-scar interfac [14-16,35] . The specific growth factors are
angiopoietin-1, β-myosin heavy chain, connexin 43, insulin like growth factor and vascular endothelial
growth. This patch is robust; it is easy to handle for open surgical or minimally invasive implantation.
Figure 1 and the Supplementary Video 1 demonstrate implantation on the epicardium in an infarcted
Yucatan mini swine via a mini median sternotomy where the patch is positioned to broadly cover all
damaged tissue. We envision that multiple patches and/or multiple patch applications could be applied
if needed. Table 1 summarizes previous work done with TE approaches using iPSC-CMs to treat heart
failure. The epicardium may play an important role in regulating regeneration and may be the catalyst
of the beneficial effects we and other investigators see when we implant cell-seeded scaffolds on the
epicardium [36-38,48-50] .

Implanting TE scaffolds in preclinical animal models of heart failure has proven safe. The data have
shown no teratoma formation, accompanied by hemodynamic benefits, and attenuated LV remodeling,
however data show limited long-term engraftment with the implanted cells despite providing immune
suppression . Menasché et al. have transplanted PSC-derived cardiac progenitor cell fibrin patches
[19]
[20]
in 6 patients with decreased LV function and showed that the treatment was safe. No arrhythmias were
noted by ICD interrogations and no tumors were reported . Based on this work, these investigators
[19]
performed a second trial of 10 patients, but these results are still forthcoming. To date, there is only one
clinical trial has commenced using PSC-CMs to treat patients in CHF; this trial is currently ongoing
[27]
in Japan . Cardiothoracic surgeons are implanting cell sheets on the epicardial surface of the heart in
immune-suppressed patients. Table 1 summarizes some of the TE scaffolds developed to treat heart failure
progressing from early work with rat neonatal cardiomyocytes to the clinical trial in Japan with PSC-CMs
on cell sheets.