Abstract
Extracellular vesicles (EVs) are reported to be involved in stem cell maintenance, self-renewal, and differentiation. Due to their bioactive cargoes influencing cell fate and function, interest in EVs in regenerative medicine has rapidly increased. EV-derived small non-coding RNA mimic the functions of the parent stem cells, regulating the maintenance and differentiation of stem cells, controlling the intercellular regulation of gene expression, and eventually affecting the cell fate. In this study, we used RNA sequencing to provide a comprehensive overview of the expression profiles of small non-coding transcripts carried by the EVs derived from human adipose tissue stromal/stem cells (AT-MSCs) and human pluripotent stem cells (hPSCs), both human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSC). Both hPSCs and AT-MSCs were characterized and their EVs were extracted using standard protocols. Small non-coding RNA sequencing from EVs showed that hPSCs and AT-MSCs showed distinct profiles, unique for each stem cell source. Interestingly, in hPSCs, most abundant miRNAs were from specific miRNA families regulating pluripotency, reprogramming and differentiation (miR-17-92, mir-200, miR-302/367, miR-371/373, CM19 microRNA cluster). For the AT-MSCs, the highly expressed miRNAs were found to be regulating osteogenesis (let-7/98, miR-10/100, miR-125, miR-196, miR-199, miR-615-3p, mir-22-3p, mir-24-3p, mir-27a-3p, mir-193b-5p, mir-195-3p). Additionally, abundant small nuclear and nucleolar RNA were detected in hPSCs, whereas Y- and tRNA were found in AT-MSCs. Identification of EV-miRNA and non-coding RNA signatures released by these stem cells will provide clues towards understanding their role in intracellular communication, and well as their roles in maintaining the stem cell niche.
Highlights
Stem cells are responsible for the development and regeneration of tissues and maintaining steady-state of organ homeostasis
It could be concluded that intercellular communication mediated by transfer of extracellular vesicles (EVs)-derived miRNAs coordinate the intercellular regulation of gene expression, which eventually affects the fate of the stem cells and their surrounding niches
Human pluripotent stem cells (PSCs) grew as well-defined colonies (Fig. 1A) and further as smooth monolayers reaching confluence, typical to undifferentiated human pluripotent stem cells (hPSCs) on laminin-521
Summary
Stem cells are responsible for the development and regeneration of tissues and maintaining steady-state of organ homeostasis. The contribution of stem cell-derived EVs in lineage commitments, maintenance of self-renewal, differentiation, maturation, efficiency of cellular reprogramming and cell fate determination are largely regulated by non-coding RNA (ncRNA)[4]. MiRNAs are small endogenous non-coding RNAs that function as posttranscriptional regulators of gene expression through translational inhibition or by promoting the degradation of mRNA. Small ncRNAs, microRNAs (miRNAs) which are central to gene regulation and cellular fate determination, can mediate their regulatory effects via EVs9. They are important regulators of reprogramming processes, maintenance of pluripotency and differentiation of stem cells[10]. Identification of EV-miRNA and other small ncRNA signatures released by these stem cells will provide clues towards understanding the role of these extracellular RNAs in intercellular communication and their role in regulation of stemness in vitro
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