Abstract
Human pluripotent stem cells harbor hope in regenerative medicine, but have limited application in treating clinical diseases due to teratoma formation. Our previous study has indicated that human umbilical cord mesenchymal stem cells (HUCMSC) can be adopted as non-teratogenenic feeders for human embryonic stem cells (hESC). This work describes the mechanism of non-tumorigenesis of that feeder system. In contrast with the mouse embryonic fibroblast (MEF) feeder, HUCMSC down-regulates the WNT/β-catenin/c-myc signaling in hESC. Thus, adding β-catenin antagonist (FH535 or DKK1) down-regulates β-catenin and c-myc expressions, and suppresses tumorigenesis (3/14 vs. 4/4, p = 0.01) in hESC fed with MEF, while adding the β-catenin enhancer (LiCl or 6-bromoindirubin-3′-oxime) up-regulates the expressions, and has a trend (p = 0.056) to promote tumorigenesis (2/7 vs. 0/21) in hESC fed with HUCMSC. Furthermore, FH535 supplement does not alter the pluripotency of hESC when fed with MEF, as indicated by the differentiation capabilities of the three germ layers. Taken together, this investigation concludes that WNT/β-catenin/c-myc pathway causes the tumorigenesis of hESC on MEF feeder, and β-catenin antagonist may be adopted as a tumor suppressor.
Highlights
Residues by an enzymatic complex of adenomatous polyposis coli (APC), Axin and the kinases glycogen synthase kinase-3β(GSK-3β) and casein kinase I, marking it for ubiquitin-mediated proteolysis
Shifting from the MEF feeder to the HUCMSC feeder reduced the expression of mRNA and protein of β-catenin in human embryonic stem cells (hESC)
Changes to the c-myc expression in hESC depended on the feeder, with down-regulation occurring when using the HUCMSC feeder, and up-regulation upon shifting back to MEF (Fig. 1a,b)
Summary
Residues by an enzymatic complex of adenomatous polyposis coli (APC), Axin and the kinases glycogen synthase kinase-3β(GSK-3β) and casein kinase I, marking it for ubiquitin-mediated proteolysis. Binding of Wnt to the cell surface Frizzled receptors and LRP5/6 co-receptors protects β-catenin from degradation, and acts on its targets, including c-myc, to promote cell cycle progression and inhibit apoptosis[13,14,15]. FH535 is a small molecule that inhibits the Wnt/β-catenin signaling pathway by antagonizing β-catenin/Tcf/LEF (T-cell factor/lymphoid enhancer factor)-mediated transcription[17], thereby inhibiting tumor cell proliferation[17]. This investigation explores the signaling pathway responsible for the HUCMSC-mediated down-regulation of c-Myc and the non-tumorigenic feature of hESC. We found that β-catenin signaling is the main factor controlling tumorigenesis, and that its inhibition mimics the tumor suppressor activity of HUCMSC
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