Background
Transplanting human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM)
tissue sheets effectively treat ischemic cardiomyopathy. Cardiac functional recovery
relies on graft survival in which angiogenesis played an important part. ONO-1301
is a synthetic prostacyclin analog with proangiogenic effects. We hypothesized that
transplantation of hiPSC-CM tissue sheets with slow-release ONO-1301 scaffold could
promote hostgraft angiogenesis, enhance tissue survival and therapeutic effect.
Methods
We developed hiPSC-CM tissue sheets with ONO-1301 slow-release scaffold and evaluated
their morphology, gene expression, and effects on angiogenesis. Three tissue sheet
layers were transplanted into a rat myocardial infarction (MI) model. Left ventricular
ejection fraction, gene expression in the MI border zone, and angiogenesis effects
were investigated 4 weeks after transplantation.
Results
In vitro assessment confirmed the slow-release of ONO-1301, and its pro-angiogenesis
effects. In addition, in vivo data demonstrated that ONO-1301 administration positively
correlated with graft survival. Cardiac tissue as thick as ∼900 μm was retained in
the ONO (+) treated group. Additionally, left ventricular ejection fraction of the
ONO (+) group was significantly enhanced, compared to ONO (−) group. The ONO (+) group
also showed significantly improved interstitial fibrosis, higher capillary density,
increased number of mature blood vessels, along with an enhanced supply of oxygen,
and nutrients.
Conclusions
Slow-release ONO-1301 scaffold provided an efficient delivery method for thick hiPSC-CM
tissue. ONO-1301 promotes angiogenesis between the host and graft and improves nutritional
and oxygen supply, thereby enhancing the survival of transplanted cells, effectively
improving ejection fraction, and therapeutic effects.
Keywords
Abbreviations:
cTnT (cardiac muscle troponin T), FS (fractional shortening), FPKM (fragments per kilobase of exon per million mapped fragments), hiPSCs (human induced pluripotent stem cells), hiPSC-CMs (human induced pluripotent stem cell-derived cardiomyocytes), HCF (human cardiac fibroblasts), HE staining (hematoxylin and eosin staining), HGF (hepatocyte growth factor), HIF-1α (hypoxia-induced factor-1 alpha (HIF1A)), HUVECs (human umbilical vein endothelial cells), HNA (human nuclear antigen), IL-6 (interleukin 6), LVEF (left ventricular ejection fraction), MI (myocardial infarction), ONO-1301SR (slow-release ONO-1301), PLGA (poly(lactic-co-glycolic acid)), PGI2 (prostacyclin or prostaglandin I2), RT-PCR (reverse transcriptase-polymerase chain reaction), SDF-1 (stromal cell-derived factor-1), TGF-β1 (transforming growth factor beta 1), TXA2 (thromboxane A2), VEGF (vascular endothelial growth factor)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: February 09, 2023
Publication stage
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