Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R2H2A6, Canada.
Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy.
Cell Death Dis. 2020 Jun 4;11(6):419. doi: 10.1038/s41419-020-2634-6.
Allogeneic mesenchymal stem cells (MSCs) are immunoprivileged and are being investigated in phase I and phase II clinical trials to treat different degenerative and autoimmune diseases. In spite of encouraging outcome of initial trials, the long-term poor survival of transplanted cells in the host tissue has declined the overall enthusiasm. Recent analyses of allogeneic MSCs based studies confirm that after transplantation in the hypoxic or ischemic microenvironment of diseased tissues, MSCs become immunogenic and are rejected by recipient immune system. The immunoprivilege of MSCs is preserved by absence or negligible expression of cell surface antigen, human leukocyte antigen (HLA)-DRα. We found that in normoxic MSCs, 26S proteasome degrades HLA-DRα and maintains immunoprivilege of MSCs. The exposure to hypoxia leads to inactivation of 26S proteasome and formation of immunoproteasome in MSCs, which is associated with upregulation and activation of HLA-DRα, and as a result, MSCs become immunogenic. Furthermore, inhibition of immunoproteasome formation in hypoxic MSCs preserves the immunoprivilege. Therefore, hypoxia-induced shift in the phenotype of proteasome from 26S toward immunoproteasome triggers loss of immunoprivilege of allogeneic MSCs. The outcome of the current study may provide molecular targets to plan interventions to preserve immunoprivilege of allogeneic MSCs in the hypoxic or ischemic environment.
同种异体间充质干细胞（MSCs）具有免疫豁免性，并正在进行 I 期和 II 期临床试验，以治疗各种退行性和自身免疫性疾病。尽管初步试验结果令人鼓舞，但移植细胞在宿主组织中的长期存活率低，降低了整体积极性。最近对同种异体 MSC 进行的分析研究证实，在患病组织缺氧或缺血的微环境中移植后，MSCs 会变得具有免疫原性，并被受者免疫系统排斥。MSCs 的免疫豁免性是通过缺乏或可忽略不计的细胞表面抗原 HLA-DRα 的表达来维持的。我们发现，在常氧 MSCs 中，26S 蛋白酶体降解 HLA-DRα，从而维持 MSCs 的免疫豁免性。暴露于缺氧会导致 26S 蛋白酶体失活，并在 MSCs 中形成免疫蛋白酶体，这与 HLA-DRα 的上调和激活有关，结果 MSCs 变得具有免疫原性。此外，抑制缺氧 MSCs 中免疫蛋白酶体的形成可保持免疫豁免性。因此，缺氧诱导的蛋白酶体表型从 26S 向免疫蛋白酶体的转变触发了同种异体 MSCs 免疫豁免性的丧失。本研究的结果可能为计划干预措施提供分子靶点，以在缺氧或缺血环境中维持同种异体 MSCs 的免疫豁免性。
