Department of Cell Biology and Physiology, UNC School of Medicine, Chapel Hill, NC 27599, USA; Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China.
Department of Cell Biology and Physiology, UNC School of Medicine, Chapel Hill, NC 27599, USA.
Biomaterials. 2022 Sep;288:121647. doi: 10.1016/j.biomaterials.2022.121647. Epub 2022 Aug 7.
Patch grafting, a novel strategy for transplantation of stem/progenitor organoids into porcine livers, has been found successful also for organoid transplantation into other normal or diseased solid organs in pigs and mice. Each organoid contained ∼100 cells comprised of biliary tree stem cells (BTSCs), co-hepato/pancreatic stem/progenitors, and partnered with early lineage stage mesenchymal cells (ELSMCs), angioblasts and precursors to endothelia and stellate cells. Patch grafting enabled transplantation into livers or pancreases of ≥10 (pigs) or ≥10 (mice) organoids/patch. Graft conditions fostered expression of multiple matrix-metalloproteinases (MMPs), especially secretory isoforms, resulting in transient loss of the organ's matrix-dictated histological features, including organ capsules, and correlated with rapid integration within a week of organoids throughout the organs and without emboli or ectopic cell distribution. Secondarily, within another week, there was clearance of graft biomaterials, followed by muted expression of MMPs, restoration of matrix-dictated histology, and maturation of donor cells to functional adult fates. The ability of patch grafts of organoids to rescue hosts from genetic-based disease states was demonstrated with grafts of BTSC/ELSMC organoids on livers, able to rescue NRG/FAH-KO mice from type I tyrosinemia, a disease caused by absence of fumaryl acetoacetate hydrolase. With the same grafts, if on pancreas, they were able to rescue NRG/Akita mice from type I diabetes, caused by a mutation in the insulin 2 gene. The potential of patch grafting for cell therapies for solid organs now requires translational studies to enable its adaptation and uses for clinical programs.
贴片移植，一种将干细胞/祖细胞类器官移植到猪肝脏中的新策略，已被证明在将类器官移植到猪和小鼠的其他正常或患病实体器官中也同样成功。每个类器官包含约 100 个细胞，由胆管树干细胞 (BTSCs)、共肝/胰腺干细胞/祖细胞组成，并与早期谱系阶段间充质细胞 (ELSMCs)、成血管细胞和内皮细胞及星状细胞前体配对。贴片移植能够将≥10 个（猪）或≥10 个（小鼠）类器官/贴片移植到肝脏或胰腺中。移植条件促进了多种基质金属蛋白酶 (MMPs) 的表达，特别是分泌型同工酶，导致器官的基质决定的组织学特征的短暂丧失，包括器官包膜，并与类器官在一周内迅速整合到整个器官中相关，没有栓塞或异位细胞分布。其次，在另一周内，移植物生物材料被清除，随后 MMPs 的表达减弱，基质决定的组织学得到恢复，供体细胞成熟为功能性成年状态。类器官贴片移植能够从遗传疾病状态中拯救宿主的能力已经通过 BTSC/ELSMC 类器官在肝脏上的移植得到证明，能够从 1 型酪氨酸血症（一种由于延胡索酰乙酰乙酸水解酶缺失引起的疾病）中拯救 NRG/FAH-KO 小鼠。用相同的移植物，如果在胰腺上，它们能够从 1 型糖尿病（一种由于胰岛素 2 基因发生突变引起的疾病）中拯救 NRG/Akita 小鼠。贴片移植为实体器官细胞治疗提供了潜力，现在需要进行转化研究，以使其适应和用于临床项目。
