title: WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors.
abstract: Tumor formation constitutes a major obstacle to the clinical application of embryonic stem cell-derived (ESC-derived) cells. In an attempt to find major extracellular signaling and intrinsic factors controlling tumorigenicity and therapeutic functionality of transplanted ESC-derived retinal progenitor cells (ESC-RPCs), we evaluated multiple kinds of ESC-RPCs in a mouse retinal degeneration model and conducted genome-wide gene expression profiling. We identified canonical WNT signaling as a critical determinant for the tumorigenicity and therapeutic function of ESC-RPCs. The function of WNT signaling is primarily mediated by TCF7, which directly induces expression of Sox2 and Nestin. Inhibition of WNT signaling, overexpression of dominant-negative Tcf7, and silencing Tcf7, Sox2, or Nestin all resulted in drastically reduced tumor formation and substantially improved retinal integration and visual preservation in mice. These results demonstrate that the WNT signaling cascade plays a critical role in modulating the tumorigenicity and functionality of ESC-derived progenitors.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Cui
authors.forename: Yuan
authors.initials: Y
authors.lastname: Guan
authors.forename: Zepeng
authors.initials: Z
authors.lastname: Qu
authors.forename: Jingfa
authors.initials: J
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Liao
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Dangsheng
authors.initials: D
authors.lastname: Li
authors.forename: Weiye
authors.initials: W
authors.lastname: Li
authors.forename: Guo-Tong
authors.initials: GT
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D005134:Eye Neoplasms / Q000378:metabolism* / Q000473:pathology; D005136:Eye Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D051538:Hepatocyte Nuclear Factor 1-alpha; D018398:Homeodomain Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D055355:Opsins / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012160:Retina / Q000473:pathology; D033581:Stem Cell Transplantation; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D060449:Wnt Signaling Pathway; D000097607:Homeobox Protein SIX3
chemical_list: D005136:Eye Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D055355:Opsins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D051822:T Cell Transcription Factor 1; D014157:Transcription Factors; D000097607:Homeobox Protein SIX3; C501127:Dkk1 protein, mouse; C496488:Hnf1a protein, mouse; C577485:Nes protein, mouse; C000605732:Pax6 protein, mouse; C105441:Rax protein, mouse