Naïve pluripotent-like characteristics of non-tumorigenic Muse cells isolated from human amniotic membrane

Abstract

Multilineage-differentiating stress-enduring (Muse) cells are non-tumorigenic pluripotent-like stem cells that exhibit triploblastic differentiation and self-renewability at the single-cell level, and are collectable as pluripotent surface marker SSEA-3(+) from the bone marrow (BM), peripheral blood, and organ connective tissues. SSEA-3(+) cells from human amniotic membrane mesenchymal stem cells (hAMSCs) were compared with hBM-Muse cells. Similar to hBM-Muse cells, hAMSC-SSEA-3(+) cells expressed pluripotency genes (OCT3/4, NANOG, and SOX2), differentiated into triploblastic cells from a single cell, self-renewed, and exhibited non-tumorigenicity. Notably, however, they exhibited unique characteristics not seen in hBM-Muse cells, including higher expression of genes related to germline- and extraembryonic cell-lineages compared with those in hBM-Muse cells in single-cell RNA-sequencing; and enhanced expression of markers relevant to germline- (PRDM14, TFAP2C, and NANOS3) and extraembryonic cell- (CDX2, GCM1, and ID2) lineages when induced by cytokine subsets, suggesting a broader differentiation potential similar to naïve pluripotent stem cells. t-SNE dimensionality reduction and Gene ontology analysis visualized hAMSC-SSEA-3(+) cells comprised a large undifferentiated subpopulation between epithelial- and mesenchymal-cell states and a small mesenchymal subpopulation expressing genes relevant to the placental formation. The AM is easily accessible by noninvasive approaches. These unique cells are a potentially interesting target naïve pluripotent stem cell-like resource without tumorigenicity.

Tumor suppressor let-7 acts as a key regulator for maintaining pluripotency gene expression in Muse cells

“…Further studies are needed to elucidate the detailed mechanisms. The telomerase activity was reported to be lower in Muse cells than that in HeLa cells and iPSCs (27,29,65). Let-7a KD stimulated the proliferation but did not increase the telomerase activity, suggesting that let-7 is a key factor for controlling cell cycle but is not directly connected to tumorigenic proliferation in Muse cells.…”

To Repair a Broken Heart: Stem Cells in Ischemic Heart Disease

“…Muse cells also exhibit reduced telomerase activity as well as increased capability for DNA repair [ 103 ]. Muse cells have been isolated from various locations, including the bone marrow (BM), connective tissues in various organs, as well as the amniotic membrane; these cells, like PSCs, are capable of differentiation into tissues from all three germ layers [ 104 ]. Use of Muse cells in animal models, including intravenous administration in a rabbit model of MI, revealed improvements in ejection fraction (EF), infarct scar size reduction and differentiation into relevant cell types [ 94 ].…”

“…Muse cells have also been utilized in human MI patients in a clinical study commenced in 2018; results showed improved ventricular function and reduced scar size, most likely due to direct cardiomyocyte differentiation as well as local paracrine effects. Nevertheless, only three patients were enrolled in this clinical study and were only followed for 12 weeks; thus, any possible tumorigenicity was not properly assessed [ 91 ], even though in general, Muse cells have been described as non-tumorigenic compared to other PSC types [ 104 , 106 ].…”

Human Muse cells isolated from preterm- and term-umbilical cord delivered therapeutic effects in rat bleomycin-induced lung injury model without immunosuppressant

“…Muse cells derived from different sources such as BM, adipose tissue, dermis, and amnion consistently exhibit pluripotency gene expression, trilineage-differentiation ability, and self-renewal at a single-cell level [21,[35][36][37]. The differentiation tendencies differ among Muse cells [21,35]: Adipose tissue-Muse cells and dermis-Muse cells express higher levels of mesodermal-and ectodermal-lineage markers than BM-Muse cells, respectively, while amnion-Muse cells show higher potential to differentiate into germ-line and extraembryonic-lineage cells compared with BM-Muse cells [36].…”

“…Muse cells derived from different sources such as BM, adipose tissue, dermis, and amnion consistently exhibit pluripotency gene expression, trilineage-differentiation ability, and self-renewal at a single-cell level [21,[35][36][37]. The differentiation tendencies differ among Muse cells [21,35]: Adipose tissue-Muse cells and dermis-Muse cells express higher levels of mesodermal-and ectodermal-lineage markers than BM-Muse cells, respectively, while amnion-Muse cells show higher potential to differentiate into germ-line and extraembryonic-lineage cells compared with BM-Muse cells [36]. While Muse cells have also been harvested from UC [38] and preterm UC yields more vigorously proliferative Muse-cell source MSCs with a higher differentiation capacity than term UC [38][39][40], the basic characteristics and therapeutic effects of preterm-and term-UC-Muse cells have not been investigated.…”