Kuroda Yasumasa, Oguma Yo, Hall Kerrigan, Dezawa Mari
Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Front Pharmacol. 2022 Oct 19;13:1027961. doi: 10.3389/fphar.2022.1027961. eCollection 2022.
Multilineage-differentiating stress enduring (Muse) cells, non-tumorigenic endogenous pluripotent stem cells, reside in the bone marrow (BM), peripheral blood, and connective tissue as pluripotent surface marker SSEA-3(+) cells. They express other pluripotent markers, including Nanog, Oct3/4, and Sox2 at moderate levels, differentiate into triploblastic lineages, self-renew at a single cell level, and exhibit anti-inflammatory effects. Cultured mesenchymal stromal cells (MSCs) and fibroblasts contain several percent of SSEA-3(+)-Muse cells. Circulating Muse cells, either endogenous or administered exogenously, selectively accumulate at the damaged site by sensing sphingosine-1-phosphate (S1P), a key mediator of inflammation, produced by damaged cells and replace apoptotic and damaged cells by spontaneously differentiating into multiple cells types that comprise the tissue and repair the tissue. Thus, intravenous injection is the main route for Muse cell treatment, and surgical operation is not necessary. Furthermore, gene introduction or cytokine induction are not required for generating pluripotent or differentiated states prior to treatment. Notably, allogenic and xenogenic Muse cells escape host immune rejection after intravenous injection and survive in the tissue as functioning cells over 6 and ∼2 months, respectively, without immunosuppressant treatment. Since Muse cells survive in the host tissue for extended periods of time, therefore their anti-inflammatory, anti-fibrotic, and trophic effects are long-lasting. These unique characteristics have led to the administration of Muse cells intravenous drip in clinical trials for stroke, acute myocardial infarction, epidermolysis bullosa, spinal cord injury, neonatal hypoxic ischemic encephalopathy, amyotrophic lateral sclerosis, and COVID-19 acute respiratory distress syndrome without HLA-matching or immunosuppressive treatment.
多谱系分化应激耐受（Muse）细胞是一种非致瘤性内源性多能干细胞，作为多能表面标志物SSEA-3(+)细胞存在于骨髓（BM）、外周血和结缔组织中。它们中等水平表达其他多能标志物，包括Nanog、Oct3/4和Sox2，可分化为三胚层谱系，在单细胞水平上自我更新，并具有抗炎作用。培养的间充质基质细胞（MSCs）和成纤维细胞含有百分之几的SSEA-3(+)-Muse细胞。循环中的Muse细胞，无论是内源性的还是外源性给予的，都能通过感知由受损细胞产生的炎症关键介质鞘氨醇-1-磷酸（S1P），选择性地在受损部位聚集，并通过自发分化为构成组织的多种细胞类型来替代凋亡和受损细胞，从而修复组织。因此，静脉注射是Muse细胞治疗的主要途径，无需手术操作。此外，在治疗前产生多能或分化状态不需要基因导入或细胞因子诱导。值得注意的是，同种异体和异种Muse细胞在静脉注射后可逃避宿主免疫排斥，分别在组织中作为功能细胞存活超过6个月和约2个月，无需免疫抑制治疗。由于Muse细胞在宿主组织中能长期存活，因此它们的抗炎、抗纤维化和营养作用是持久的。这些独特的特性使得在中风、急性心肌梗死、大疱性表皮松解症、脊髓损伤、新生儿缺氧缺血性脑病、肌萎缩侧索硬化症和COVID-19急性呼吸窘迫综合征的临床试验中，无需进行HLA匹配或免疫抑制治疗即可静脉滴注Muse细胞。
