Ectopic expansion and vascularization of engineered hepatic tissue based on heparinized acellular liver matrix and mesenchymal stromal cell spheroids
Ectopic expansion and vascularization of engineered hepatic tissue based on heparinized acellular liver matrix and mesenchymal stromal cell spheroids
复制标题
基于肝素化无细胞肝基质和间充质基质细胞球体的工程肝组织的异位扩张和血管化。
DOI：
10.1016/j.actbio.2021.10.017
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发表时间：
2021-12-11
影响因子：
9.7
通讯作者：
Bu，Hong
中科院分区：
文献类型：
--
作者：
Wu，Qiong;Li，Yi;Bu，Hong
工程肝器官发生尚不是一种可行的治疗选择，但异位肝组织发生是可能的。越来越多的证据表明，细胞-细胞相互作用和细胞-基质相互作用在决定体外和体内工程肝组织的特性中起着重要作用。在本研究中，我们利用肝素化脱细胞肝支架和骨髓间充质间质细胞球体来制造工程化肝组织，随后将其植入有或无肝损伤的Sprague-Dawley大鼠网膜。评估移植肝细胞样细胞在异位肝系统中的存活率、肝脏特异性功能、分化水平和再生潜力，以及工程肝组织的血管化状态和治疗潜力。我们证明了这些肝移植物能够在异位肝系统中存活并具有肝细胞特异性功能，同时也能有效地与宿主血管网络吻合。此外，我们发现，在肝脏受损的免疫功能强的大鼠中，移植物内的肝细胞样细胞在4周内扩大了9倍以上。免疫染色显示这些肝细胞样细胞在体内可以自组织成绳状结构。此外，这些肝移植物在CCl4诱导的肝损伤中显示出治疗潜力。据我们所知，这是第一个证明基于去细胞化的肝支架和干细胞在异位位置产生长期血管化肝实质的报告。这些结果为工程肝组织从构建到移植提供了一种经济可行的方法。该方法可应用于临床医学，特别是代谢性肝病。在这篇文章中，我们提出了一种肝工程组织（HET）从构建到移植的优化方法。该方法的核心是利用肝素化脱细胞肝支架与干细胞球体的结合，为体外和体内HETin提供必要的细胞-细胞和细胞-细胞外基质相互作用。我们证明了这些肝移植物在异位肝系统中具有肝细胞特异性功能和较强的增殖活性，并且能够有效地与宿主血管网络吻合，与宿主免疫系统相容。这种方法可能有一天应用于临床医学，特别是代谢性肝病。
Engineered liver organogenesis is not yet a viable therapeutic option, but ectopic liver histogenesis may be possible. Accumulating evidence has suggested that cell-cell interactions and cell-matrix interactions play an important role in determining the properties of engineered hepatic tissuein vitroandin vivo. In the current study, we utilized heparinized decellularized liver scaffolds and bone marrow mesenchymal stromal cell spheroids to fabricate engineered hepatic tissue, which was subsequently implanted into the omentum of Sprague-Dawley rats with or without liver injury. The survival, liver-specific functions, differentiation level and regenerative potential of the implanted hepatocyte-like cells in this ectopic liver system were evaluated, together with the vascularization status and therapeutic potential of the engineered hepatic tissue. We demonstrated that these hepatic grafts could survive and possess hepatocyte specific function in this ectopic liver system but could also efficiently anastomose with host vascular networks. Furthermore, we found that hepatocyte-like cells within grafts expanded more than 9-fold over the course of 4 weeks in immunocompetent rats with injured livers. Immunostaining revealed that these hepatocyte-like cells could self-organize into cord-like structuresin vivo. In addition, these hepatic grafts exhibited therapeutic potential in liver injury induced by CCl4. To our knowledge, this is the first report demonstrating the generation of long-term vascularized hepatic parenchyma at ectopic sites based on decellularized liver scaffolds and stem cells. These results provide an economic and feasible method for engineering hepatic tissue from construction to transplantation. This methodology may be applicable in clinical medicine, especially metabolic liver diseases.Statement of significanceIn this manuscript, we presented an optimized method for the hepatic engineered tissue (HET) from construction to transplantation. The core of this method is utilizing the combination of heparinized decellularized liver scaffolds and stem cell spheroids, which could provide necessary cell-cell and cell-extracellular matrix interactions for HETin vitroandin vivo. We proved that these hepatic grafts could possess hepatocyte specific function and exhibit strong proliferative activity in ectopic liver system, but also able to anastomose with the host vascular networks efficiently and be compatible with the host immune system. This methodology may be possible one day to apply in clinical medicine, especially metabolic liver diseases.