Temporal Dynamics of Metabolic Acquisition in Grafted Engineered Human Liver Tissue.
Temporal Dynamics of Metabolic Acquisition in Grafted Engineered Human Liver Tissue.
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DOI：
10.1002/adbi.202200208
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发表时间：
2023-05
期刊：
影响因子：
3.7
通讯作者：
Stevens, Kelly R.
中科院分区：
文献类型：
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作者：
Fortin, Chelsea L.;McCray, Tara N.;Saxton, Sarah H.;Johansson, Fredrik;Andino, Christian B.;Mene, Jonathan;Wang, Yuliang;Stevens, Kelly R.
肝病影响着全球数百万人，终末期肝衰竭只能通过器官移植来治愈。不幸的是，供体器官日益短缺，不同人群之间公平获得移植的机会也存在差异。目前，全球移植需求的满足率不足 10%，凸显了对替代疗法的需求。补充器官功能的工程肝组织移植物可以满足这些需求。虽然由水凝胶包裹的人类肝细胞、内皮细胞和成纤维细胞构建的工程肝组织之前已成功移植到啮齿动物模型中，但这些组织表达人类肝脏代谢基因和蛋白质的程度仍然未知。在这里，我们构建了工程化的人类肝脏组织，并通过 RNA 测序、组织学和宿主血清学在植入后的连续阶段表征了它们的植入、扩张和代谢表型。在第 1-2 周观察代谢基因的表达，然后在第 4-9.5 周观察细胞组织成肝索。此外，移植的工程组织表现出已知在天然人类肝脏中分区的关键功能蛋白的渐进空间限制性表达。据我们所知，这是植入体内后工程化人类肝脏组织分区的第一份报告，这可能对该领域具有重要的转化意义。成功改造的人类肝脏组织应该具有与天然肝脏相同的功能并且在结构上类似于天然肝脏。这包括模仿肝脏组织的“分区”特征，即在不同的区域发挥不同的作用。在这里，我们描述了植入啮齿类动物体内的工程人类肝脏组织的时程评估，并证明了代谢蛋白的分区表型。
Liver disease affects millions globally and end-stage liver failure is only cured by organ transplant. Unfortunately, there is a growing shortage of donor organs and disparities in equitable access to transplants among different populations. Less than 10% of global transplantation needs are currently met, highlighting the demand for alternative therapies. Engineered liver tissue grafts that supplement organ function could address these demands. While engineered liver tissues built from human hepatocytes, endothelial cells, and fibroblasts encased in hydrogel have been successfully engrafted in rodent models previously, the extent to which these tissues express human liver metabolic genes and proteins remains unknown. Here, we built engineered human liver tissues and characterized their engraftment, expansion, and metabolic phenotype at sequential stages post-implantation by RNA sequencing, histology, and host serology. Expression of metabolic genes was observed at weeks 1–2, followed by cellular organization into hepatic cords by weeks 4–9.5. Furthermore, grafted engineered tissues exhibited progressive spatially restricted expression of critical functional proteins known to be zonated in the native human liver. To our knowledge, this is the first report of engineered human liver tissue zonation after implantation in vivo, which could have important translational implications for this field. Successfully engineered human liver tissue should perform functions of and structurally resemble the native liver. This includes mimicking the characteristic of liver tissue known as “zonation”, where different roles are carried out in distinct regions. Here we describe a time-course evaluation of engineered human liver tissue implanted in rodents in vivo and demonstrate a zonated phenotype of metabolic proteins.
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