Lack of CD47 on donor hepatocytes promotes innate immune cell activation and graft loss: a potential barrier to hepatocyte xenotransplantation.
Lack of CD47 on donor hepatocytes promotes innate immune cell activation and graft loss: a potential barrier to hepatocyte xenotransplantation.
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DOI：
10.3727/096368913x663604
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发表时间：
2014-03
影响因子：
3.3
通讯作者：
Yang YG
中科院分区：
文献类型：
--
作者：
Navarro-Alvarez N;Yang YG
我们之前已经表明，CD47 的种间不相容性在触发巨噬细胞对异种造血细胞的排斥中起着重要作用。然而，CD47 不相容性是否也会引起非造血细胞异种移植物的排斥仍不清楚。在此，我们在肝细胞移植的小鼠模型中解决了这个问题，其中使用 CD47−/− 肝细胞来模拟 CD47 不相容性的异种移植物。我们发现，与非移植对照相比，将 CD47−/−（而非野生型（WT））肝细胞脾内移植到部分肝切除的同基因 WT 小鼠中，导致具有激活表型（即 Mac-1+CD14+ 和 Mac-1+CD16/32high）的 Mac-1+ 细胞快速增加。此外，CD47−/− 肝细胞比 WT 肝细胞受损更严重，如这些小鼠中较高的 AST 和 ALT 血清水平所示。此外，在接受WT肝细胞的小鼠中观察到长期供体肝细胞存活和肝脏再增殖，而CD47−/−肝细胞在2周内被完全排斥。这些结果表明，供体肝细胞上的 CD47 可以防止受体骨髓先天免疫细胞激活，从而有助于肝细胞移植后移植物的存活。因此，CD47 不相容性可能会给肝细胞异种移植带来额外的障碍。
We have previously shown that interspecies incompatibility of CD47 plays an important role in triggering rejection of xenogeneic hematopoietic cells by macrophages. However, whether CD47 incompatibility also induces rejection of non-hematopoietic cellular xenografts remains unknown. Herein, we have addressed this question in a mouse model of hepatocyte transplantation, in which CD47−/− hepatocytes were used to resemble xenografts for CD47 incompatibility. We show that intrasplenic transplantation of CD47−/−, but not wild-type (WT), hepatocytes into partially hepatectomized syngeneic WT mice resulted in a rapid increase in Mac-1+ cells with an activation phenotype (i.e., Mac-1+CD14+ and Mac-1+CD16/32high), compared to non-transplant controls. In addition, CD47−/− hepatocytes were more severely damaged than WT hepatocytes, as indicated by the greater AST and ALT serum levels in these mice. Furthermore, long-term donor hepatocyte survival and liver repopulation were observed in mice receiving WT hepatocytes, whereas CD47−/− hepatocytes were completely rejected within 2 weeks. These results suggest that CD47 on donor hepatocytes prevents recipient myeloid innate immune cell activation, hence aiding in graft survival after hepatocyte transplantation. Thus, CD47 incompatibility is likely to present an additional barrier to hepatocyte xenotransplantation.