Abstract
To realize human induced pluripotent stem cell (hiPSC)-based cardiac regenerative therapy, evidence of therapeutic advantages in human-sized diseased hearts are indispensable. In combination with an efficient and simultaneous differentiation of various cardiac lineages from hiPSCs and cell sheet technology, we aimed to generate clinical-sized large cardiac tissue sheets (L-CTSs) and to evaluate the therapeutic potential in porcine infarct heart. We simultaneously induced cardiomyocytes (CMs) and vascular cells [vascular endothelial cells (ECs) and vascular mural cells (MCs)] from hiPSCs. We generated L-CTSs using 10cm-sized temperature-responsive culture dishes. We induced myocardial infarction (MI) in micromini-pigs (15–25 kg) and transplanted the L-CTSs (Tx) 2 weeks after MI induction (4 sheets/recipient) under immunosuppression (Tx: n = 5, Sham: n = 5). Self-pulsating L-CTSs were approximately 3.5cm in diameter with 6.8×106±0.8 of cells containing cTnT+-CMs (45.6±13.2%), VE-cadherin+-ECs (5.3±4.4%) and PDGFRβ+-MCs (14.4±20.7%), respectively (n = 5). In Tx group, echocardiogram indicated a significantly higher systolic function of the left ventricle (LV) compared to that in sham control (Sham vs Tx: fractional shortening: 24.2±8.6 vs 40.5±9.7%; p<0.05). Ejection fraction evaluated by left ventriculogram was significantly higher in Tx group (25.3±6.2% vs 39.8±4.2%; p<0.01). Speckle tracking echocardiogram showed a significant increase of circumference strain in infarct and border regions after transplantation. Fibrotic area was significantly lower in Tx group (23.8±4.5 vs 15.9±3.8%; P<0.001). Capillary density in the border region was significantly higher in Tx group (75.9±42.6/mm2 vs 137.4±44.8/mm2, p<0.001). These data indicate that the L-CTS transplantation attenuated LV remodeling. L-CTSs potentially restore cardiac dysfunction of human-sized infarct heart.
Highlights
Cardiovascular diseases remain a major cause of death and increasing the burden of healthcare worldwide, especially in the Western world [1]
Pluripotent stem cells (PSCs) [embryonic stem cells (ESCs) / induced pluripotent stem cells] -derived defined cardiovascular cell populations are considered to serve as a novel cell sources for cardiac regenerative therapy by virtue of theoretically infinite proliferative potential of PSCs [4, 5] and novel capacity to differentiate into various cardiovascular cell populations including cardiomyocytes (CMs), vascular endothelial cells (ECs) and vascular mural cells (MCs) [6,7,8]
The large cardiac tissue sheets (L-CTSs) consisted with 6.8×106±0.8 (n = 5) of cells containing cardiac isoform of Troponin T (cTnT)+-CMs (45.6±13.2%), VE-cadherin+-ECs (5.3±4.4%) and PDGFRβ+-MCs (14.4±20.7%) (n = 5)
Summary
Cardiovascular diseases remain a major cause of death and increasing the burden of healthcare worldwide, especially in the Western world [1]. The transplantation of heart tissue-mimetic cell sheets including defined cardiovascular cell populations (cardiac tissue sheets; CTSs) for sub-acute myocardial infarction (MI) rat models using mouse ESC- and human iPSC-derived cardiovascular cell populations have consistently demonstrated an excellent functional recovery of cardiac functional deterioration after MI [8, 10] These proof-of-concept studies in small animals may represent the potential effectiveness of CTSs for the functional recovery from cardiac injury and may open the door for the realization of cardiac regenerative therapy using the CTS technology, verification of the therapeutic potential in clinical scaled injured hearts similar to the human heart would be required for clinical application of this strategy
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