Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
J Cell Physiol. 2021 Sep;236(9):6328-6343. doi: 10.1002/jcp.30299. Epub 2021 Jan 28.
Although the autologously transplanted cells are immunologically durable, allogeneic cell transplantation is inevitable in a series of cases. Mesenchymal stem cells (MSCs) are one of the suitable candidates for cardiac tissue regeneration that have been shown to acquire immunogenicity concurrent with cardiomyogenic differentiation. The present study aimed to exploit PD-L1, as a key immunomodulatory checkpoint ligand to protect the MSCs-derived cardiomyocyte-like cells (CLCs) against the detrimental alloimmunity. Mouse bone marrow-derived MSCs were stably transduced to overexpress PD-L1. MSCs were in vitro differentiated into CLCs and the expressions of immunologic molecules were compared between MSCs and CLCs. The in vitro and in vivo allogeneic immune responses were also examined. The differentiated CLCs had higher expressions of MHC-I and CD80. Upon in vitro coculture with allogeneic splenocytes, CLCs caused more CD4 and CD8 T cell activation, lymphocyte proliferation, and interferon-γ (IFN-γ) release in comparison to MSCs. PD-L1 overexpression on CLCs decreased the activation of CD8 T cells, proliferation of lymphocytes, and release of IFN-γ. The PD-L1-overexpressing CLCs elicited lower in vivo CD4 and CD8 T cell activation and reduced the anti-donor antibody response accompanied by increased durability and reduced T cell infiltration. The present study verified the potential of PD-L1 overexpression as a preparative strategy for the protection of allogeneic MSCs-derived CLCs against the detrimental alloreaction.
虽然自体移植细胞具有免疫持久性，但在一系列情况下不可避免地需要进行同种异体细胞移植。间充质干细胞（MSCs）是一种适合用于心肌组织再生的候选细胞，已证明其在向心肌细胞分化的同时获得免疫原性。本研究旨在利用 PD-L1 作为关键的免疫调节检查点配体，来保护 MSC 来源的心肌样细胞（CLCs）免受有害的同种异体免疫反应的影响。将小鼠骨髓来源的 MSC 稳定转染以过表达 PD-L1。将 MSC 体外分化为 CLCs，并比较 MSC 和 CLCs 之间免疫分子的表达。还检测了体外和体内的同种异体免疫反应。分化的 CLCs 具有更高的 MHC-I 和 CD80 表达。与同种异体脾细胞体外共培养时，与 MSC 相比，CLC 引起更多的 CD4 和 CD8 T 细胞激活、淋巴细胞增殖和干扰素-γ（IFN-γ）释放。在 CLCs 上过表达 PD-L1 可降低 CD8 T 细胞的激活、淋巴细胞的增殖和 IFN-γ的释放。过表达 PD-L1 的 CLCs 引起体内 CD4 和 CD8 T 细胞激活水平降低，抗供体抗体反应减少，同时耐久性增加，T 细胞浸润减少。本研究验证了过表达 PD-L1 作为保护同种异体 MSC 来源的 CLCs 免受有害同种异体反应的一种预备策略的潜力。
