Department of Obstetrics and Gynecology, Cardinal Tien Hospital, New Taipei, Taiwan.
School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan.
Cell Biol Int. 2021 May;45(5):1072-1081. doi: 10.1002/cbin.11553. Epub 2021 Feb 2.
Mesenchymal stem cells (MSCs) play an important role as immune modulator through interaction with several immune cells, including macrophages. In this study, the immunomodulatory potency of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) was demonstrated in the in vivo middle cerebral artery occlusion (MCAo)-induced brain injury rat model and in vitro THP-1-derived macrophages model. At 24 h after induction of MCAo, hUC-MSCs was administered via tail vein as a single dose. Remarkably, hUC-MSCs could inhibit M1 polarization and promote M2 polarization of microglia in vivo after 14 days induction of MCAo. Compared with THP-1-derived macrophages which had been stimulated by lipopolysaccharide, the secretion of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interferon-γ inducible protein (IP-10), were significantly reduced in the presence of hUC-MSCs. Moreover, the secretion of anti-inflammatory cytokine, interleukin-10 (IL-10), was significantly increased after cocultured with hUC-MSCs. Prostaglandins E2 (PGE2), secreted by hUC-MSCs, is one of the crucial immunomodulatory factors and could be inhibited in the presence of COX2 inhibitor, NS-398. PGE2 inhibition suppressed hUC-MSCs immunomodulatory capability, which was restored after addition of synthetic PGE2, establishing the minimum amount of PGE2 required for immunomodulation. In conclusion, our data suggested that PGE2 is a crucial potency marker involved in the therapeutic activity of hUC-MSCs through macrophages immune response modulation and cytokines regulation. This study provides the model for the development of a surrogate quantitative potency assay of immunomodulation in stem cells production.
间充质干细胞（MSCs）通过与多种免疫细胞（包括巨噬细胞）相互作用，发挥重要的免疫调节作用。在这项研究中，我们在体内大脑中动脉闭塞（MCAo）诱导的脑损伤大鼠模型和体外 THP-1 衍生的巨噬细胞模型中证明了人脐带来源的间充质干细胞（hUC-MSCs）的免疫调节功效。在诱导 MCAo 后 24 小时，通过尾静脉单次给予 hUC-MSCs。值得注意的是，在诱导 MCAo 14 天后，hUC-MSCs 可以抑制体内小胶质细胞的 M1 极化并促进其 M2 极化。与经脂多糖刺激的 THP-1 衍生的巨噬细胞相比，hUC-MSCs 存在时，促炎细胞因子肿瘤坏死因子-α（TNF-α）和干扰素-γ诱导蛋白（IP-10）的分泌明显减少。此外，与 hUC-MSCs 共培养后，抗炎细胞因子白细胞介素-10（IL-10）的分泌明显增加。前列腺素 E2（PGE2）是由 hUC-MSCs 分泌的一种重要免疫调节因子，在 COX2 抑制剂 NS-398 的存在下可被抑制。PGE2 抑制降低了 hUC-MSCs 的免疫调节能力，在添加合成 PGE2 后恢复，确定了免疫调节所需的 PGE2 的最小量。总之，我们的数据表明，PGE2 是一种关键的效力标志物，通过调节巨噬细胞免疫反应和细胞因子调节，参与 hUC-MSCs 的治疗活性。本研究为开发干细胞生产中免疫调节的替代定量效力测定提供了模型。
