TY - JOUR
T1 - Mechanical stimulation enhances development of scaffold-free, 3D-printed, engineered heart tissue grafts
AU - Lui, Cecillia
AU - Chin, Alexander F.
AU - Park, Seungman
AU - Yeung, Enoch
AU - Kwon, Chulan
AU - Tomaselli, Gordon
AU - Chen, Yun
AU - Hibino, Narutoshi
N1 - Funding Information:
We thank Deborah DiSilvestre for cell culture assistance and differentiation of hiPSCs. This work was financially supported by the Irene Piccinini Investigator Research Fellowship (to C.L.), the National Institutes of Health T32 grant T32HL007227 (to C.L. via Johns Hopkins Department of Cardiology), and the Johns Hopkins Magic that Matters Fund (to N.H.).
Publisher Copyright:
© 2021 John Wiley & Sons Ltd.
PY - 2021/5
Y1 - 2021/5
N2 - Current efforts to engineer a clinically relevant tissue graft from human-induced pluripotent stem cells (hiPSCs) have relied on the addition or utilization of external scaffolding material. However, any imbalance in the interactions between embedded cells and their surroundings may hinder the success of the resulting tissue graft. Therefore, the goal of our study was to create scaffold-free, 3D-printed cardiac tissue grafts from hiPSC-derived cardiomyocytes (CMs), and to evaluate whether or not mechanical stimulation would result in improved graft maturation. To explore this, we used a 3D bioprinter to produce scaffold-free cardiac tissue grafts from hiPSC-derived CM cell spheroids. Static mechanical stretching of these grafts significantly increased sarcomere length compared to unstimulated free-floating tissues, as determined by immunofluorescent image analysis. Stretched tissue was found to have decreased elastic modulus, increased maximal contractile force, and increased alignment of formed extracellular matrix, as expected in a functionally maturing tissue graft. Additionally, stretched tissues had upregulated expression of cardiac-specific gene transcripts, consistent with increased cardiac-like cellular identity. Finally, analysis of extracellular matrix organization in stretched grafts suggests improved remodeling by embedded cardiac fibroblasts. Taken together, our results suggest that mechanical stretching stimulates hiPSC-derived CMs in a 3D-printed, scaffold-free tissue graft to develop mature cardiac material structuring and cellular fates. Our work highlights the critical role of mechanical conditioning as an important engineering strategy toward developing clinically applicable, scaffold-free human cardiac tissue grafts.
AB - Current efforts to engineer a clinically relevant tissue graft from human-induced pluripotent stem cells (hiPSCs) have relied on the addition or utilization of external scaffolding material. However, any imbalance in the interactions between embedded cells and their surroundings may hinder the success of the resulting tissue graft. Therefore, the goal of our study was to create scaffold-free, 3D-printed cardiac tissue grafts from hiPSC-derived cardiomyocytes (CMs), and to evaluate whether or not mechanical stimulation would result in improved graft maturation. To explore this, we used a 3D bioprinter to produce scaffold-free cardiac tissue grafts from hiPSC-derived CM cell spheroids. Static mechanical stretching of these grafts significantly increased sarcomere length compared to unstimulated free-floating tissues, as determined by immunofluorescent image analysis. Stretched tissue was found to have decreased elastic modulus, increased maximal contractile force, and increased alignment of formed extracellular matrix, as expected in a functionally maturing tissue graft. Additionally, stretched tissues had upregulated expression of cardiac-specific gene transcripts, consistent with increased cardiac-like cellular identity. Finally, analysis of extracellular matrix organization in stretched grafts suggests improved remodeling by embedded cardiac fibroblasts. Taken together, our results suggest that mechanical stretching stimulates hiPSC-derived CMs in a 3D-printed, scaffold-free tissue graft to develop mature cardiac material structuring and cellular fates. Our work highlights the critical role of mechanical conditioning as an important engineering strategy toward developing clinically applicable, scaffold-free human cardiac tissue grafts.
KW - engineered heart tissue
KW - human-induced pluripotent stem cells (hiPSCs)
KW - maturation
KW - mechanical microenvironment
KW - tissue engineering
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U2 - 10.1002/term.3188
DO - 10.1002/term.3188
M3 - Article
C2 - 33749089
AN - SCOPUS:85103928310
SN - 1932-6254
VL - 15
SP - 503
EP - 512
JO - Journal of Tissue Engineering and Regenerative Medicine
JF - Journal of Tissue Engineering and Regenerative Medicine
IS - 5
ER -