三维组织工程化人心肌细胞亚细胞纳米结构的研究
Probing Subcellular Nanostructure of Engineered Human Cardiomyocytes in 3D Tissue
摘要：
人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）的结构和功能成熟对于应用于药物测试、疾病建模和最终治疗用途是必不可少的。多细胞3D组织平台改善了hiPSC-CM的功能成熟，但在3D环境中探测心脏收缩特性仍然具有挑战性，特别是在深度和活组织中。使用小角X射线散射（SAXS）图像，我们表明，hiPSC-CM，成熟和在3D环境中检查，表现出周期性的肌丝晶格的空间排列，这是以前没有检测到的hiPSC-CM。收缩力被发现与散射强度（R2=0.44）和晶格间距（R2=0.46）。散射强度也与晶格间距（R2=0.81），表明我们的结构测量相对于功能测量的噪声较低。值得注意的是，我们观察到肌丝突变导致肥厚型心肌病（HCM）的组织中肌丝有序性降低。我们的研究结果突出了人类心脏组织工程的进展，并使前所未有的研究hiPSC-CM的结构成熟。
英文摘要：
The structural and functional maturation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is essential for application to pharmaceutical testing, disease modeling, and ultimately therapeutic use. Multicellular 3D-tissue platforms have improved functional maturation of hiPSC-CMs, but probing cardiac contractile properties remains challenging in a 3D environment, especially at depth and in live tissues. Using small angle X-ray scattering (SAXS) images, we show that hiPSC-CMs, matured and examined in a 3D environment, exhibit periodic spatial arrangement of the myofilament lattice, which has not been previously detected in hiPSC-CMs. Contractile force is found to correlate with both scattering intensity (R2=0.44) and lattice spacing (R2=0.46). Scattering intensity also correlates with lattice spacing (R2=0.81), suggestive of lower noise in our structural measurement relative to the functional measurement. Notably, we observe decreased myofilament ordering in tissues with a myofilament mutation known to lead to hypertrophic cardiomyopathy (HCM). Our results highlight the progress of human cardiac tissue engineering and enable unprecedented study of structural maturation in hiPSC-CMs.
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