Generation and maturation of human iPSC-derived 3D organotypic cardiac microtissues in long-term culture.
Generation and maturation of human iPSC-derived 3D organotypic cardiac microtissues in long-term culture.
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DOI：
10.1038/s41598-022-22225-w
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发表时间：
2022-10-18
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
心血管疾病仍然是全世界死亡的主要原因；因此，越来越多的人关注于开发适合研究个性化医学和临床前试验的生理相关的体外心血管组织模型。尽管最近取得了一些进展，但能够同时复制组织复杂性和成熟度的模型仍然有限。我们已经建立了一个无支架的方案，在体外从hipsc中产生多细胞，跳动的人类心脏微组织，即人类器官型心脏微组织（hocts），显示出一定程度的自组织，可以长期培养。这是通过hiPSC在2D单层培养中向心血管谱系分化，然后在3D低附着培养皿中进一步聚集来实现的。生成的hocmt包含多种细胞类型，这些细胞在生理上构成心脏并在没有外部刺激的情况下跳动超过100天。我们已经证明，与标准的单层心脏分化相比，3D hOCMTs显示出更好的心脏规格、存活和代谢成熟。我们还通过长期培养对心脏活性药物的反应证实了hOCMTs的功能。此外，我们证明它们可以用于研究化疗诱导的心脏毒性。随着培养时间的延长，我们的三维显微组织显示出自组织、细胞异质性和功能的趋势，我们也可以确认这些结构为人类心脏类器官（hCOs）。该研究有助于开发更多与生理相关的心脏组织模型，并为未来心血管生物学的转化研究提供了强大的平台。
Cardiovascular diseases remain the leading cause of death worldwide; hence there is an increasing focus on developing physiologically relevant in vitro cardiovascular tissue models suitable for studying personalized medicine and pre-clinical tests. Despite recent advances, models that reproduce both tissue complexity and maturation are still limited. We have established a scaffold-free protocol to generate multicellular, beating human cardiac microtissues in vitro from hiPSCs—namely human organotypic cardiac microtissues (hOCMTs)—that show some degree of self-organization and can be cultured for long term. This is achieved by the differentiation of hiPSC in 2D monolayer culture towards cardiovascular lineage, followed by further aggregation on low-attachment culture dishes in 3D. The generated hOCMTs contain multiple cell types that physiologically compose the heart and beat without external stimuli for more than 100 days. We have shown that 3D hOCMTs display improved cardiac specification, survival and metabolic maturation as compared to standard monolayer cardiac differentiation. We also confirmed the functionality of hOCMTs by their response to cardioactive drugs in long-term culture. Furthermore, we demonstrated that they could be used to study chemotherapy-induced cardiotoxicity. Due to showing a tendency for self-organization, cellular heterogeneity, and functionality in our 3D microtissues over extended culture time, we could also confirm these constructs as human cardiac organoids (hCOs). This study could help to develop more physiologically-relevant cardiac tissue models, and represent a powerful platform for future translational research in cardiovascular biology.
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影响因子：
5
作者：
Cho S;Lee C;Skylar-Scott MA;Heilshorn SC;Wu JC
通讯作者：
Wu JC
影响因子：
6.1
作者：
Grosberg A;Alford PW;McCain ML;Parker KK
通讯作者：
Parker KK
影响因子：
16.6
作者：
Andersen P;Tampakakis E;Jimenez DV;Kannan S;Miyamoto M;Shin HK;Saberi A;Murphy S;Sulistio E;Chelko SP;Kwon C
通讯作者：
Kwon C
影响因子：
4.6
作者：
Grancharova T;Gerbin KA;Rosenberg AB;Roco CM;Arakaki JE;DeLizo CM;Dinh SQ;Donovan-Maiye RM;Hirano M;Nelson AM;Tang J;Theriot JA;Yan C;Menon V;Palecek SP;Seelig G;Gunawardane RN
通讯作者：
Gunawardane RN
影响因子：
3.5
作者：
Dolci, Alberto;Dominici, Roberto;Panteghini, Mauro
通讯作者：
Panteghini, Mauro