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CHIR99021 Promotes hiPSC-Derived Cardiomyocyte Proliferation in Engineered 3D Microtissues
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2021-09-09 , DOI: 10.1002/adhm.202100926 Ramona Hesselbarth 1 , Tilman U Esser 1 , Kaveh Roshanbinfar 1 , Stefan Schrüfer 2 , Dirk W Schubert 2 , Felix B Engel 1
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2021-09-09 , DOI: 10.1002/adhm.202100926 Ramona Hesselbarth 1 , Tilman U Esser 1 , Kaveh Roshanbinfar 1 , Stefan Schrüfer 2 , Dirk W Schubert 2 , Felix B Engel 1
Affiliation
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Cardiac tissue engineering is a promising strategy to generate human cardiac tissues for modeling cardiac diseases, screening for therapeutic drugs, and repairing the injured heart. Yet, several issues remain to be resolved including the generation of tissues with high cardiomyocyte density. Here, it is shown that the integration of the glycogen synthase kinase-3β inhibitor CHIR99021 in collagen I hydrogels promotes proliferation of human-induced pluripotent stem cell-derived (hiPSC) cardiomyocytes post-fabrication improving contractility of and calcium flow in engineered 3D cardiac microtissues. CHIR99021 has no effect on the gelation kinetics or the mechanical properties of collagen I hydrogels. Analysis of cell density and proliferation based on Ki-67 staining indicates that integration of CHIR99021 together with external CHIR99021 stimulation increases hiPSC-cardiomyocyte number by ≈2-fold within 7 d post-fabrication. Analysis of the contractility of engineered cardiac tissues after another 3 d in the absence of external CHIR99021 shows that CHIR99021-induced hiPSC-cardiomyocyte proliferation results in synchronized calcium flow, rhythmic beating, increased speed of contraction and contraction amplitude, and reduced peak-to-peak time. The CHIR99021-stimulated engineered cardiac microtissues exhibit spontaneous rhythmic contractions for at least 35 d. Collectively, the data demonstrate the potential of induced cardiomyocyte proliferation to enhance engineered cardiac microtissues by increasing cardiomyocyte density.
中文翻译：
CHIR99021 在工程化 3D 微组织中促进 hiPSC 衍生的心肌细胞增殖
心脏组织工程是一种很有前景的策略，可以生成人类心脏组织，用于模拟心脏病、筛选治疗药物和修复受伤的心脏。然而，仍有几个问题有待解决，包括产生具有高心肌细胞密度的组织。在这里，表明糖原合酶激酶-3 β的整合胶原蛋白 I 水凝胶中的抑制剂 CHIR99021 促进制造后人诱导多能干细胞衍生 (hiPSC) 心肌细胞的增殖，改善工程 3D 心脏微组织的收缩性和钙流。CHIR99021 对胶原蛋白 I 水凝胶的凝胶动力学或机械性能没有影响。基于 Ki-67 染色的细胞密度和增殖分析表明，CHIR99021 与外部 CHIR99021 刺激的整合使 hiPSC 心肌细胞数量在制造后 7 天内增加约 2 倍。在没有外部 CHIR99021 的情况下，再过 3 天后对工程化心脏组织的收缩力分析表明，CHIR99021 诱导的 hiPSC-心肌细胞增殖导致钙流同步、节律性跳动、增加收缩速度和收缩幅度，减少峰峰值时间。CHIR99021 刺激的工程心脏微组织表现出至少 35 天的自发节律性收缩。总的来说，这些数据证明了诱导心肌细胞增殖通过增加心肌细胞密度来增强工程心脏微组织的潜力。
更新日期：2021-10-21
中文翻译：
CHIR99021 在工程化 3D 微组织中促进 hiPSC 衍生的心肌细胞增殖
心脏组织工程是一种很有前景的策略，可以生成人类心脏组织，用于模拟心脏病、筛选治疗药物和修复受伤的心脏。然而，仍有几个问题有待解决，包括产生具有高心肌细胞密度的组织。在这里，表明糖原合酶激酶-3 β的整合胶原蛋白 I 水凝胶中的抑制剂 CHIR99021 促进制造后人诱导多能干细胞衍生 (hiPSC) 心肌细胞的增殖，改善工程 3D 心脏微组织的收缩性和钙流。CHIR99021 对胶原蛋白 I 水凝胶的凝胶动力学或机械性能没有影响。基于 Ki-67 染色的细胞密度和增殖分析表明，CHIR99021 与外部 CHIR99021 刺激的整合使 hiPSC 心肌细胞数量在制造后 7 天内增加约 2 倍。在没有外部 CHIR99021 的情况下，再过 3 天后对工程化心脏组织的收缩力分析表明，CHIR99021 诱导的 hiPSC-心肌细胞增殖导致钙流同步、节律性跳动、增加收缩速度和收缩幅度，减少峰峰值时间。CHIR99021 刺激的工程心脏微组织表现出至少 35 天的自发节律性收缩。总的来说，这些数据证明了诱导心肌细胞增殖通过增加心肌细胞密度来增强工程心脏微组织的潜力。
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