WNT/β-Catenin signaling pathway regulates non-tumorigenesis of human embryonic stem cells co-cultured with human umbilical cord mesenchymal stem cells.
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.
Department of Pediatrics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, R.O.C.|Lab of stem cell research, Department of Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, R.O.C.|Institue of Medical Science, Tzu Chi University, Hualien, Taiwan.
Yu-Hsun
YH
Chang
Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Taiwan, R.O.C.|Cervical Cancer Prevention Center, Department of Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, R.O.C.|Institue of Medical Science, Tzu Chi University, Hualien, Taiwan.
Tang-Yuan
TY
Chu
Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Taiwan, R.O.C.|Lab of stem cell research, Department of Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, R.O.C.|Institue of Medical Science, Tzu Chi University, Hualien, Taiwan.
Dah-Ching
DC
Ding
D000818:Animals; D063646:Carcinogenesis; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin