Scaffold-Free Tubular Engineered Heart Tissue From Human Induced Pluripotent Stem Cells Using Bio-3D Printing Technology in vivo

Abstract

Engineered heart tissues (EHTs) that are fabricated using human induced pluripotent stem cells (hiPSCs) have been considered as potential cardiac tissue substitutes in case of heart failure. In the present study, we have created hiPSC-derived cardiac organoids (hiPSC-COs) comprised of hiPSC-derived cardiomyocytes, human umbilical vein endothelial cells, and human fibroblasts. To produce a beating conduit for patients suffering from congenital heart diseases, we constructed scaffold-free tubular EHTs (T-EHTs) using hiPSC-COs and bio-3D printing with needle arrays. The bio-3D printed T-EHTs were cut open and transplanted around the abdominal aorta as well as the inferior vena cava (IVC) of NOG mice. The transplanted T-EHTs were covered with the omentum, and the abdomen was closed after completion of the procedure. Additionally, to compare the functionality of hiPSC-COs with that of T-EHTs, we transplanted the former around the aorta and IVC as well as injecting them into the subcutaneous tissue on the back of the mice. After 1 m of the transplantation procedures, we observed the beating of the T-EHTs in the mice. In histological analysis, the T-EHTs showed clear striation of the myocardium and vascularization compared to hiPSC-COs transplanted around the aorta or in subcutaneous tissue. Based on these results, bio-3D-printed T-EHTs exhibited a better maturation in vivo as compared to the hiPSC-COs. Therefore, these beating T-EHTs may form conduits for congenital heart disease patients, and T-EHT transplantation can form a treatment option in such cases.

Accelerated Cardiac Aging in Patients With Congenital Heart Disease

“…Moreover, pharmacological modulation of altered pathways could be applied to reduce autologous stem cells senescence ex vivo , in order to enhance their reparative ability upon implantation ( 154 ). The readers are directed to recent reviews and preclinical studies on this topic ( 19 , 20 , 133 , 155 , 156 ).…”

Human Engineered Heart Tissue Models for Disease Modeling and Drug Discovery

“…Arai et al developed a bio-3D printer technology and fabricated scaffold-free cellular constructs with 3D-laminating spheroids on a micro-needle array ( Arai et al, 2020 ; Kawai et al, 2021 ). They generated an array with a 3D design by arranging the micro-needles to line up with the spheroids, revealing a robust assessment of contractile properties and drug response.…”

Enhancing Stem Cell-Based Therapeutic Potential by Combining Various Bioengineering Technologies

“…Importantly, 3D bioprinting of autologous iPSC-derived cells or tissues may not cause immune rejection or infection with organ transplants. Therefore, Kawai et al (2021) recently developed scaffold-free tubular heart tissues using 3D bioprinting techniques with iPSCs-derived cardiomyocytes, human umbilical vein endothelial cells, and human fibroblasts. The beating of these 3D-bioprinted heart tissues was observed in mice with clear striations of the myocardium and vascularization after 1 month post-transplantation ( Kawai et al, 2021 ).…”

“…Therefore, Kawai et al (2021) recently developed scaffold-free tubular heart tissues using 3D bioprinting techniques with iPSCs-derived cardiomyocytes, human umbilical vein endothelial cells, and human fibroblasts. The beating of these 3D-bioprinted heart tissues was observed in mice with clear striations of the myocardium and vascularization after 1 month post-transplantation ( Kawai et al, 2021 ). Zhang et al used 3D-bioprinted endothelial cells within microfibrous hydrogel scaffolds to form a layer of confluent endothelium ( Zhang Y. S. et al, 2016 ).…”