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Bio-Design and Manufacturing  2021 Vol.4 No.4 P.790-805

http://doi.org/10.1007/s42242-021-00137-4


Biofabrication ofsize?controlled liver microtissues incorporated withECM?derived microparticles toprolong hepatocyte function


Author(s):  ZahraHeydari, IbrahimZarkesh, Mohammad?HosseinGhanian, MahdokhtH.Aghdaei, SvetlanaKotova, EnsiehZahmatkesh, ZahraFarzaneh, AbbasPiryaei, ImanAkbarzadeh, AnastasiaShpichka, RobertoGramignoli, PeterTimashev, HosseinBaharvand, MassoudVosough

Affiliation(s):  Department ofDevelopmental Biology, University ofScience andCulture, ACECR, 14155-4364Tehran, Iran; more

Corresponding email(s):   masvos@royaninstitute.org

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ZahraHeydari, IbrahimZarkesh, Mohammad?HosseinGhanian, MahdokhtH.Aghdaei, SvetlanaKotova, EnsiehZahmatkesh, ZahraFarzaneh, AbbasPiryaei, ImanAkbarzadeh, AnastasiaShpichka, RobertoGramignoli, PeterTimashev, HosseinBaharvand, MassoudVosough. Biofabrication ofsize?controlled liver microtissues incorporated withECM?derived microparticles toprolong hepatocyte function[J]. Journal of Zhejiang University Science D, 2021, 4(4): 790-805.

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journal="Journal of Zhejiang University Science D",
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Abstract: 
Multicellular microtissues of primary human hepatocytes (PHHs) co-cultured with other supporting cell types are a promising model for drug screening and toxicological studies. However, these liver microtissues (LMs) rapidly lose their functions during exvivo culture. Here, in order to mimic the cellular and structural hepatic microenvironment, we co-cultured PHHs with human mesenchymal stromal cells (MSCs) and human umbilical vein endothelial cells (HUVECs) in the presence of cell-sized microparticles (MPs) derived from liver extracellular matrix (LEMPs). The microwell culture platform enabled biofabrication of size-controlled multicellular microtissues (PHH:HUVEC:MSC=3:2:1) with efcient LEMP incorporation (about 70% at a 2:1 ratio of cells:MP). The biofabricated liver microtissues (BLMs) were cultured exvivo for 14days and compared to the cell-only LM in terms of gene and protein expression, functional activity, cytochrome P450 (CYP450) enzyme inducibility, and drug sensitivity. The results supported superior hepatic-related gene expression, functional activity, and polarity for PHH in BLM compared to LM. CYP450 enzyme inducibility and dose-responsive sensitivity to toxic drugs were signifcantly higher in the BLM group. In conclusion, microtissue engineering by incorporation of tissue-specifc microparticles within a multicellular microtissue can ofer some advantages for drug discovery studies and cell transplantation applications. In the near future, this approach could generate a scalable platform of several functional biofabricated microtissues representing diferent organs.

伊朗Massoud Vosough等 | 生物制造尺寸可控的肝脏微组织与细胞外基质衍生的微粒相结合用以延长肝细胞功能

本研究论文聚焦人工制造的肝微组织在体外的性能提升研究。与其他支持细胞类型共培养的原代人肝细胞(PHHs)的多细胞微组织是药物筛选和毒理学研究的候选模型。然而,这些肝脏微组织(LMs)在离体培养期间会迅速失去其功能。在本研究中,为了模拟细胞和结构肝脏微环境,我们制造了以肝脏细胞外基质(LMP)为原料的细胞大小的微粒(MPs),与人间充质基质细胞(MSCs)和人脐静脉内皮细胞(HUVECs)共培养原代肝细胞。微孔培养平台能够以高效的LEMP整合(细胞:微粒=2:1下约为70%)对尺寸控制的多细胞微组织(PHH:HUVEC:MSC=3:2:1)进行生物制造。将制造的肝微组织离体培养14天,并在基因和蛋白质表达、功能活性、细胞色素P450(CYP450)酶诱导性和药物敏感性方面与纯细胞肝微组织进行比较。与纯细胞肝微组织相比,结果显示肝相关基因表达、功能活性和PHH在制造的肝组织中具有优越性。制造组的CYP450酶诱导性和对毒性药物的剂量反应敏感性显著较高。总之,通过在多细胞微组织中掺入组织特异性微粒的微组织工程可以为药物发现研究和细胞移植应用提供一些优势。在不久的将来,这种方法可以生成一个可扩展的平台,包含不同器官的几种功能性生物制造微组织。

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