Graduate Institute of Life Sciences, National Defense Medical Center (NDMC), Taipei, Taiwan, Republic of China.
Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan, Taiwan, Republic of China.
Stem Cells. 2018 Jun;36(6):903-914. doi: 10.1002/stem.2795. Epub 2018 Feb 12.
Multilineage tissue-source mesenchymal stem cells (MSCs) possess strong immunomodulatory properties and are excellent therapeutic agents, but require constant isolation from donors to combat replicative senescence. The differentiation of human induced pluripotent stem cells (iPSCs) into MSCs offers a renewable source of MSCs; however, reports on their immunomodulatory capacity have been discrepant. Using MSCs differentiated from iPSCs reprogrammed using diverse cell types and protocols, and in comparison to human embryonic stem cell (ESC)-MSCs and bone marrow (BM)-MSCs, we performed transcriptome analyses and assessed for functional immunomodulatory properties. Differentiation of MSCs from iPSCs results in decreased c-Myc expression and its downstream pathway along with a concomitant downregulation in the DNA replication pathway. All four lines of iPSC-MSCs can significantly suppress in vitro activated human peripheral blood mononuclear cell (PBMC) proliferation to a similar degree as ESC-MSCs and BM-MSCs, and modulate CD4 T lymphocyte fate from a type 1 helper T cell (Th1) and IL-17A-expressing (Th17) cell fate to a regulatory T cell (Treg) phenotype. Moreover, iPSC-MSCs significantly suppress cytotoxic CD8 T proliferation, activation, and differentiation into type 1 cytotoxic T (Tc1) and IL-17-expressing CD8 T (Tc17) cells. Coculture of activated PBMCs with human iPSC-MSCs results in an overall shift of secreted cytokine profile from a pro-inflammatory environment to a more immunotolerant milieu. iPSC-MSC immunomodulation was also validated in vivo in a mouse model of induced inflammation. These findings support that iPSC-MSCs possess low oncogenicity and strong immunomodulatory properties regardless of cell-of-origin or reprogramming method and are good potential candidates for therapeutic use. Stem Cells 2018;36:903-914.
多能组织源间充质干细胞（MSCs）具有强大的免疫调节特性，是优秀的治疗剂，但为了对抗复制性衰老，需要不断从供体中分离。人诱导多能干细胞（iPSCs）分化为 MSCs 提供了可再生的 MSC 来源；然而，关于其免疫调节能力的报告结果并不一致。使用使用不同细胞类型和方案重编程的 iPSCs 分化的 MSCs 与人类胚胎干细胞（ESC）-MSCs 和骨髓（BM）-MSCs 进行比较，我们进行了转录组分析并评估了其功能免疫调节特性。iPSCs 分化为 MSCs 导致 c-Myc 表达及其下游途径减少，同时 DNA 复制途径下调。所有四条 iPSC-MSCs 线都能显著抑制体外激活的人外周血单个核细胞（PBMC）增殖，抑制程度与 ESC-MSCs 和 BM-MSCs 相似，并调节 CD4 T 淋巴细胞命运从 1 型辅助 T 细胞（Th1）和表达 IL-17A 的（Th17）细胞命运向调节性 T 细胞（Treg）表型。此外，iPSC-MSCs 还能显著抑制细胞毒性 CD8 T 细胞增殖、活化，并分化为 1 型细胞毒性 T（Tc1）和表达 IL-17 的 CD8 T（Tc17）细胞。激活的 PBMC 与人类 iPSC-MSCs 共培养会导致细胞因子分泌谱从促炎环境向更免疫耐受的环境整体转变。在诱导炎症的小鼠模型中也验证了 iPSC-MSC 的免疫调节作用。这些发现支持 iPSC-MSCs 具有低致瘤性和强大的免疫调节特性，无论其起源细胞或重编程方法如何，都是治疗应用的良好候选者。Stem Cells 2018;36:903-914.
