Abstract
One of the major challenges in cell-based cardiac regenerative medicine is the in vitro construction of three-dimensional (3D) tissues consisting of induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) and a blood vascular network supplying nutrients and oxygen throughout the tissue after implantation. We have successfully built a vascularized iPSC-CM 3D-tissue using our validated cell manipulation technique. In order to evaluate an availability of the 3D-tissue as a biomaterial, functional morphology of the tissues was examined by light and transmission electron microscopy through their implantation into the rat infarcted heart. Before implantation, the tissues showed distinctive myofibrils within iPSC-CMs and capillary-like endothelial tubes, but their profiles were still like immature. In contrast, engraftment of the tissues to the rat heart led the iPSC-CMs and endothelial tubes into organization of cell organelles and junctional apparatuses and prompt development of capillary network harboring host blood supply, respectively. A number of capillaries in the implanted tissues were derived from host vascular bed, whereas the others were likely to be composed by fusion of host and implanted endothelial cells. Thus, our vascularized iPSC-CM 3D-tissues may be a useful regenerative paradigm which will require additional expanded and long-term studies.
Highlights
Ischemic heart disease is responsible for many deaths worldwide[1]
We have recently improved this cell-accumulation technique to fabricate a 3D induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) tissue with synchronous and periodic beating and found that the introduction of normal human cardiac fibroblasts (NHCFs) into induced pluripotent stem cells (iPSCs)-CM tissues plays an important role in modulating organization and synchronous beating depending on the proportion of NHCFs22
In order to evaluate applicability of our vascularized iPSC-CM 3D-tissues as an implantation material for regenerative medicine, the present study demonstrates their morphological characteristics and alteration through implantation to the cardiac infarction model
Summary
Ischemic heart disease is responsible for many deaths worldwide[1]. various advanced therapies have been developed for the cardiac disorder, it is so far impossible to revive the function of the necrotic myocardium because of reduced ability of mature cardiac muscle cells to proliferate and regenerate[2,3]. Direct engraftment of a large amount of iPSC-CMs into the target area of the heart remains a significant problem as to how to supply oxygen and nutrients into the graft for survival of the iPSC-CMs10,11 To address this problem, a cell sheet of the iPSC-CMs has been developed and reported to cause a beneficial effect on cardiac function through a paracrine effect after implantation to the infarcted porcine heart[12]. Since myocardia is well known to need abundant oxygen and nutrients to maintain their functions and structures, it is readily anticipated that thick iPSC-CM tissue implants result in their shortage within the implants, only depending on passive diffusion from the surrounding tissue This is likely to eventuate in severe tissue damages involving cellular necrosis and a low cell survival ratio[15,16]. We have recently improved this cell-accumulation technique to fabricate a 3D iPSC-CM tissue with synchronous and periodic beating and found that the introduction of normal human cardiac fibroblasts (NHCFs) into iPSC-CM tissues plays an important role in modulating organization and synchronous beating depending on the proportion of NHCFs22
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