Synergistic effect of three‐dimensional coculture and photobiomodulation therapy on vascularized liver spheroid formation by stem cells,Journal of Cellular Physiology

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Synergistic effect of three‐dimensional coculture and photobiomodulation therapy on vascularized liver spheroid formation by stem cells
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-01-11 , DOI: 10.1002/jcp.30270
In-Su Park ₁

Affiliation

Despite studies reporting functional differentiation of liver cells, a three‐dimensional, vascularized liver organ has yet to be developed from mesenchymal stem cells. We investigated whether treatment with photobiomodulation (PBM) before three‐dimensional liver spheroid transplantation improved the recovery of liver function via stimulation of angiogenesis and hepatocyte differentiation. Liver spheroids composed of hepatic, endothelial, and mesenchymal cells were subjected to PBM therapy. To evaluate the in vivo therapeutic effect of the liver spheroids treated with PBM, phosphate‐buffered saline, liver spheroid, and PBM‐treated liver spheroid were transplanted into a damaged host liver using conventional chimeric mouse models. To further characterize the maturation of transplanted PBM‐liver spheroid compared with the newly generated non‐PBM‐liver spheroid or human liver tissues, the expression profiles of mature liver signature genes were analyzed. Liver spheroids expressed hepatocyte growth factors, including vascular endothelial growth factor and angiogenic factors. The cells in liver spheroid compensated for the low viability and improved the function of hepatocytes. Here, we demonstrate the formation of vascularized and functional human liver spheroid from human adipose‐derived stem cells by transplantation of liver tissue created in vitro. Albumin secretion by PBM‐treated liver spheroid was higher on Day 28 compared with liver spheroid‐seeded transplant group. PBM‐liver spheroids serve as individual vascularization units, promoting the simultaneous development of new microvascular networks at different locations inside the implanted tissue constructs. The vasculature in the liver spheroid transplants became functional by connecting to the host vessels within 48 h. These PBM‐liver spheroids may be useful in designing artificial three‐dimensional hepatic tissue constructs and in cell therapy with limited numbers of human hepatocytes.

中文翻译：

三维共培养和光生物调节疗法对干细胞血管化肝球体形成的协同作用

尽管研究报告了肝细胞的功能分化，但尚未从间充质干细胞中开发出三维的、血管化的肝器官。我们研究了在三维肝球体移植前进行光生物调节 (PBM) 治疗是否通过刺激血管生成和肝细胞分化来改善肝功能的恢复。对由肝细胞、内皮细胞和间充质细胞组成的肝球体进行 PBM 治疗。为了评估用 PBM 处理的肝球体的体内治疗效果，使用常规嵌合小鼠模型将磷酸盐缓冲盐水、肝球体和 PBM 处理的肝球体移植到受损的宿主肝脏中。为了进一步表征移植的 PBM 肝球体与新生成的非 PBM 肝球体或人肝组织相比的成熟度，我们分析了成熟肝脏特征基因的表达谱。肝球体表达肝细胞生长因子，包括血管内皮生长因子和血管生成因子。肝球体中的细胞弥补了低活力并改善了肝细胞的功能。在这里，我们证明了通过移植体外产生的肝组织，从人脂肪干细胞形成血管化和功能性人肝球体。与肝球体种子移植组相比，PBM 处理的肝球体在第 28 天分泌的白蛋白更高。PBM-肝球体作为单个血管化单位，促进在植入组织结构内的不同位置同时开发新的微血管网络。肝球体移植物中的脉管系统通过在 48 小时内连接到宿主血管而发挥功能。这些 PBM 肝球体可用于设计人工三维肝组织结构和有限数量的人类肝细胞的细胞治疗。

更新日期：2021-01-11

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