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Review
. 2021;7(4):219-228.
doi: 10.1007/s40778-021-00201-w. Epub 2021 Oct 6.

Sensing Stemness

Teresa V Bowman  1   2   3 , Eirini Trompouki  4   5
Affiliations
Review

Sensing Stemness

Teresa V Bowman et al. Curr Stem Cell Rep. 2021.

Abstract

Purpose of review: Hematopoietic stem cells (HSCs) are formed embryonically during a dynamic developmental process and later reside in adult hematopoietic organs in a quiescent state. In response to their changing environment, HSCs have evolved diverse mechanisms to cope with intrinsic and extrinsic challenges. This review intends to discuss how HSCs and other stem cells co-opted DNA and RNA innate immune pathways to fine-tune developmental processes.

Recent findings: Innate immune receptors for nucleic acids like the RIG-I-like family receptors and members of DNA sensing pathways are expressed in HSCs and other stem cells. Even though the "classic" role of these receptors is recognition of foreign DNA or RNA from pathogens, it was recently shown that cellular transposable element (TE) RNA or R-loops activate such receptors, serving as endogenous triggers of inflammatory signaling that can shape HSC formation during development and regeneration.

Summary: Endogenous TEs and R-loops activate RNA and DNA sensors, which trigger distinct inflammatory signals to fine-tune stem cell decisions. This phenomenon could have broad implications for diverse somatic stem cells, for a variety of diseases and during aging.

Keywords: DNA sensors; Hematopoietic stem cells; Plasticity; R-loops; RNA sensors; Transposable elements.

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Conflict of interest statement

Conflict of InterestTeresa V. Bowman and Eirini Trompouki declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
A RIG-I-Like receptors (RLRs), such as MDA5 and RIG-I, are activated by numerous cytosolic ligands, such as mitochondrial RNA (mtRNA), 5′-triphosphate RNA, dsRNA, and transposable element transcripts (TEs). cGAS is stimulated in both the cytoplasm and nucleus by several endogenous stimuli, such as micronuclei, mitochondrial DNA (mtDNA), RNA:DNA hybrids, cytosolic chromatin fragments (CCF), naked cytosolic DNA, stalled ribosomes, and most recently RNA. Activation of RLRs promotes oligomerization with the mitochondrial anti-viral signaling protein (MAVS), which triggers activation of kinases like Tank Binding Kinase 1 (TBK1) and IκB kinase ε (IKKε). Stimuli binding to cGAS induces its synthetase activity resulting in production of the second messenger cyclic GMP-AMP (cGAMP). STING activation by cGAMP results in induction of TBK1. Stimulation of either RNA or DNA sensor pathways can ultimately result in the translocation of Interferon Response Factor 3 (IRF3), IRF7, and nuclear factor kappa B (NF-κB) to the nucleus leading to the induction of an IFN response and the secretion of proinflammatory cytokines. Cells possess negative regulators of the sensor pathways including LGP2 and ADAR1 for RLRs and nucleosome tethering and the circular RNA cia-cGAS for nuclear cGAS. B Nucleic acid sensor activation alters stem cell homeostasis in cell-type and context-specific manners. Pathway activation can result in diverse cellular outcomes, such as expansion, exhaustion, senescence, or cell death. Created with BioRender.com
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