The impact of transposable element activity on therapeutically relevant human stem cells

Abstract

Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapies.

Horizontal Gene Transfer: From Evolutionary Flexibility to Disease Progression

“…It has been reported that∼124 LINE-1mediated insertions can cause specific genetic diseases (Hancks and Kazazian, 2016), different types of cancer (Babaian and Mager, 2016), and neurodegenerative diseases (Tam et al, 2019). They also adversely affect the prospect of stem cell-based therapies (Schumann et al, 2019).…”

“…Human stem cells are indispensable for most basic, clinical, and translational research, such as gene therapy and regenerative medicine. However, they are wider in the clinic and are still limited by their potential risks due to genomic instability and tumorigenesis concerns (Schumann et al, 2019).…”

“…Also, the L1 RNA is required for repression of the transcriptional program specific to the 2-cell embryo and promotes exit from the 2-cell stage (Percharde et al, 2018). Genotoxicity concerns for retrotransposon-mediated gene transfer are contradictory and reviewed in detail elsewhere (Schumann et al, 2019).…”

“…Besides cancer, TEs are also implicated in the pathogenesis of various well-known genetic- (Payer and Burns, 2019), metabolic- (Turcot et al, 2012;Costello and Schones, 2018;Castellano-Castillo et al, 2019), and neurological (Saleh et al, 2019;Tam et al, 2019) diseases. Moreover, LINE insertion which promotes genomic instability may pose a threat to the biosafety of stem cells which serve as valuable resources for regenerative medicine and cell-based therapies (Schumann et al, 2019). Importantly, recent data indicates that the mammalian genome has undergone a HGT related to exosomes that can affect the therapeutic efficacy of modern genome editing tools, such as clustered regularly interspaced short palindromic repeat (CRISPR) (Ono et al, 2019).…”

Transposable Element-Gene Splicing Modulates the Transcriptional Landscape of Human Pluripotent Stem Cells

“…Consequently, it is important to understand how TEs contribute to the coding and non-coding transcriptome (You et al 2017;Ma et al 2019;Morillon and Gautheret 2019), if hPSCs are to be used in cell replacement therapy (Fort et al 2014;Schumann et al 2019). However, due to limitations in short-read based sequencing, accurate transcriptome maps have been elusive.…”