Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2

Abstract

<jats:p>Stemness encompasses the capability of a cell for self-renewal and differentiation. The stem cell maintains a balance between proliferation, quiescence, and regeneration via interactions with the microenvironment. Previously, we showed that ectopic expression of the mitochondrial ribosomal protein S18-2 (MRPS18-2) led to immortalization of primary fibroblasts, accompanied by induction of an embryonic stem cell (ESC) phenotype. Moreover, we demonstrated interaction between S18-2 and the retinoblastoma-associated protein (RB) and hypothesized that the simultaneous expression of RB and S18-2 is essential for maintaining cell stemness. Here, we experimentally investigated the role of S18-2 in cell stemness and differentiation. Concurrent expression of RB and S18-2 resulted in immortalization of<jats:italic>Rb1</jats:italic><jats:sup>−/−</jats:sup>primary mouse embryonic fibroblasts and in aggressive tumor growth in severe combined immunodeficiency mice. These cells, which express both RB and S18-2 at high levels, exhibited the potential to differentiate into various lineages in vitro, including osteogenic, chondrogenic, and adipogenic lineages. Mechanistically, S18-2 formed a multimeric protein complex with prohibitin and the ring finger protein 2 (RNF2). This molecular complex increased the monoubiquitination of histone H2A<jats:sup>Lys119</jats:sup>, a characteristic trait of ESCs, by enhanced E3-ligase activity of RNF2. Furthermore, we found enrichment of KLF4 at the<jats:italic>S18-2</jats:italic>promoter region and that the<jats:italic>S18-2</jats:italic>expression is positively correlated with<jats:italic>KLF4</jats:italic>levels. Importantly, knockdown of S18-2 in zebrafish larvae led to embryonic lethality. Collectively, our findings suggest an important role for S18-2 in cell stemness and differentiation and potentially also in cancerogenesis.</jats:p>

Comparative characteristic study from bone marrow-derived mesenchymal stem cells

“…Stemness, a natural property of MSCs, refers to the capacity of MSCs to maintain self-renewal and an undifferentiated state [ 42 ]. Stemness is important for quiescence, proliferation, and regeneration through the interaction between MSCs and their microenvironment [ 42 43 ].…”

Non-stem bladder cancer cell-derived extracellular vesicles promote cancer stem cell survival in response to chemotherapy

“…Recent studies have shown that ribosomes are involved in multiple biological processes, such as cellular proliferation, differentiation, homeostasis, and development of cancer [ 40 , 42 , 43 ]. Undifferentiated CSCs are known to maintain low levels of global translation and degradation activity, but they need to respond to dynamic alterations in the tumor environment during disease progression by rapidly regulating protein translational programs [ 44 – 46 ]. Maintaining the ability of CSCs to undergo self-renewal requires high translation efficiency [ 41 , 45 , 47 ], and inhibiting translation in CSCs has the potential to reduce their stem-like properties [ 48 ].…”

Self-Healing Hydrogels: Preparation, Mechanism and Advancement in Biomedical Applications

“…According to Cheung et al stem cells are proposed to exist in a proliferative or quiescent state [176]. A stem cell encompasses the capability for self-renewal and differentiation through a balance between self-renewing proliferation, differentiate into tissue-specific cell type and quiescence via microenvironment interactions [177]. The microenvironment interactions are governed via ECM mechanics, engineered matrix degradation, cell-adhesive ligands, ECM microstructure, cell-cell interactions, cell-secreted factors, heterologous cell interactions (Figure 12).…”