FOXP1 circular RNA sustains mesenchymal stem cell identity via microRNA inhibition

Abstract

Stem cell identity and plasticity are controlled by master regulatory genes and complex circuits also involving non-coding RNAs. Circular RNAs (circRNAs) are a class of RNAs generated from protein-coding genes by backsplicing, resulting in stable RNA structures devoid of free 5’ and 3’ ends. Little is known of the mechanisms of action of circRNAs, let alone in stem cell biology. In this study, for the first time, we determined that a circRNA controls mesenchymal stem cell (MSC) identity and differentiation. High-throughput MSC expression profiling from different tissues revealed a large number of expressed circRNAs. Among those, circFOXP1 was enriched in MSCs compared to differentiated mesodermal derivatives. Silencing of circFOXP1 dramatically impaired MSC differentiation in culture and in vivo. Furthermore, we demonstrated a direct interaction between circFOXP1 and miR-17–3p/miR-127–5p, which results in the modulation of non-canonical Wnt and EGFR pathways. Finally, we addressed the interplay between canonical and non-canonical Wnt pathways. Reprogramming to pluripotency of MSCs reduced circFOXP1 and non-canonical Wnt, whereas canonical Wnt was boosted. The opposing effect was observed during generation of MSCs from human pluripotent stem cells. Our results provide unprecedented evidence for a regulatory role for circFOXP1 as a gatekeeper of pivotal stem cell molecular networks.

Differential Regulation of circRNA, miRNA, and piRNA during Early Osteogenic and Chondrogenic Differentiation of Human Mesenchymal Stromal Cells

“…Another interesting target is represented by the LPAR1 gene, encoding for a lysophosphatidic acid receptor, whose absence has been previously shown to decrease bone mass [49]. Furthermore, the downregulation of circular FOXP1 in osteogenic differentiation (identified by RNAseq) is in accordance with a recent study that suggested a role for this circRNA in maintaining MSCs in a multipotent state [50].…”

<p>Biological Roles and Mechanisms of Circular RNA in Human Cancers</p>

“…A direct interaction between circFOXP1 and miR-17-3p/miR-127-5p resulted in the modulation of the epidermal growth factor receptor (EGFR) and noncanonical Wnt pathways suggesting the regulatory role for circFOXP1 as a gatekeeper of pivotal stem cell molecular networks. 241 In addition, the underlying correlation between circRNAs and cancer stem cells (CSCs) has been reported in HCC. For example, the absence of circZKSCAN1 endowed several malignant properties including cancer stemness and closely correlated with poor overall and recurrence-free survival in HCC.…”

Five Decades Later, Are Mesenchymal Stem Cells Still Relevant?

“…Therefore, it is expected that the combinatorial analysis of such markers will allow to circumscribe defined subsets of perivascular progenitors, as well as their MSC progeny, ideally suited for the regeneration of discrete cell lineages and tissues, notwithstanding whether this healing effect is consecutive to cellfor-cell replacement, secretion of free or microvesicle-packaged growth factors, or a combination of these actions. Importantly, better understanding of the molecular control of MSC activity and ensuing manipulation thereof should also improve the therapeutic utilization of these cells (Shen et al, 2017;Cherubini et al, 2019;Meyers et al, 2019a).…”