Inhibition of β-catenin–TCF1 interaction delays differentiation of mouse embryonic stem cells

Abstract

The ability of mouse embryonic stem cells (mESCs) to self-renew or differentiate into various cell lineages is regulated by signaling pathways and a core pluripotency transcriptional network (PTN) comprising Nanog, Oct4, and Sox2. The Wnt/β-catenin pathway promotes pluripotency by alleviating T cell factor TCF3-mediated repression of the PTN. However, it has remained unclear how β-catenin’s function as a transcriptional activator with TCF1 influences mESC fate. Here, we show that TCF1-mediated transcription is up-regulated in differentiating mESCs and that chemical inhibition of β-catenin/TCF1 interaction improves long-term self-renewal and enhances functional pluripotency. Genetic loss of TCF1 inhibited differentiation by delaying exit from pluripotency and conferred a transcriptional profile strikingly reminiscent of self-renewing mESCs with high Nanog expression. Together, our data suggest that β-catenin’s function in regulating mESCs is highly context specific and that its interaction with TCF1 promotes differentiation, further highlighting the need for understanding how its individual protein–protein interactions drive stem cell fate.

Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus

“…Deletion of Tcf1 did not affect pluripotent gene expression in mESCs (S6D Fig) as expected [49], and in contrast with another report [50]. …”

Extracellular matrix derived from periodontal ligament cells maintains their stemness and enhances redifferentiation via the wnt pathway

“…Moreover, many growth factors are present in a cell‐derived ECM, which may represent another reason for its superior qualities. In this study, we found decreased levels of ROS in the ECM group compared with those in the control group, which was consistent with other studies . Intracellular ROS play a critical role in cell survival.…”

“…In recent years, studies have indicated that young systemic environments can rejuvenate the reseeding of stem cells. Many researchers have begun to focus on the use of a tissue‐specific ECM as an in vitro expansion material . In this study, we have successfully fabricated a PDLC‐derived ECM system on 2 D substrates, and investigated the effect of this ECM on the pluripotency and osteogenic potential of high‐passage PDLCs.…”

“…Several studies have revealed that a decellularized ECM derived from mesenchymal cells promotes the proliferation of reseeded cells, maintains their stemness, and enhances tissue‐specific differentiation . Following in vivo transplantation, these cells exhibit a higher regeneration capacity than those expanded on plastic .…”

Dynamic expression of tRNA‐derived small RNAs define cellular states

“…Gene body coverage analysis, for all samples, showed reads covering the entire transcript and not from one specific region. We mined publicly available transcriptome data [65] and classified transcripts that were more than twofold upregulated after RA treatment as "differentiation-responsive genes" and more than twofold downregulated as "pluripotency-associated genes". We used a cut-off of DESeq normalized value > 200 in at least one of the four samples (Scr1 and tsRNA pulldown in LIF and RA).…”