Immunogenicity of induced pluripotent stem cell-derived smooth muscle cells results from a reduction in the expression of indoleamine 2,3 dioxygenase (IDO-1)

Smooth muscle cells (SMCs) derived from allogeneic induced pluripotent stem cells (iPSC) hold significant potential in cellular therapy for many cardiovascular diseases. However, their immunological profile is poorly characterized, limiting their clinical progression.
This study aimed to investigate the immunogenicity of iPSC-SMC in comparison with naturally derived vascular SMCs (v-SMCs).
We found iPSC-SMCs, in contrast to naturally derived vascular SMCs (v-SMC), triggered T effector memory (TEM) cell proliferation. However, expression of TEM activation-related proteins was comparable between both cell types. Since arterial v-SMCs can also establish immunoprivilege through indoleamine 2,3 dioxygenase (IDO-1) activity, we therefore investigated IDO-1 expression in two independently engineered iPSC-SMCs (NIBSC 8 (N8) and Yale 6 (Y6)). IDO-1 expression and functionality was markedly reduced in both iPSC-SMC lines compared to v-SMC and unlike v-SMC, neither iPSC-SMC line could modulate the immune response in a co-culture with CD3/CD28 activated peripheral blood mononuclear cells (PBMC).
These results indicate that iPSC-SMC’s impaired ability to modulate the immune response through IDO-1 expression contributes to their differing immunogenicity to v-SMC and highlights the importance of immune phenotyping for therapeutic applications of iPSC-derivatives.

源自同种异体诱导多能干细胞（induced pluripotent stem cells，iPSC）的平滑肌细胞（smooth muscle cells，SMCs）在多种心血管疾病的细胞治疗中具有显著应用潜力。然而，其免疫相关特征尚未得到充分阐明，限制了其临床转化进程。
本研究旨在对比天然来源血管平滑肌细胞（vascular SMCs，v-SMCs），探究iPSC来源SMC的免疫原性。
研究发现，与天然来源血管平滑肌细胞不同，iPSC-SMC可触发效应记忆T细胞（T effector memory，TEM）增殖。不过，两种细胞类型中TEM激活相关蛋白的表达水平并无显著差异。鉴于动脉血管平滑肌细胞可通过吲哚胺2,3-双加氧酶（indoleamine 2,3 dioxygenase，IDO-1）活性建立免疫豁免，我们因此对两株独立构建的iPSC-SMC（NIBSC 8，即N8；Yale 6，即Y6）的IDO-1表达情况进行了检测。结果显示，与血管平滑肌细胞相比，两株iPSC-SMC的IDO-1表达与功能均显著降低；且与血管平滑肌细胞不同，两株iPSC-SMC均无法在与CD3/CD28激活的外周血单个核细胞（peripheral blood mononuclear cells，PBMC）的共培养体系中调节免疫应答。
上述结果表明，iPSC-SMC通过IDO-1表达调节免疫应答的能力受损，这是其与血管平滑肌细胞免疫原性存在差异的原因，同时也凸显了对iPSC衍生细胞开展免疫表型分析以用于治疗应用的重要性。