• Cancer stem cells
• Drug resistance
• Hepatocellular carcinoma
• Self-renewal
• Targeted therapy

• Humans
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Drug Resistance, Neoplasm/drug effects
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Animals
• Molecular Targeted Therapy/methods

• extracellular vesicles
• lipid metabolism
• retinal organoids
• retinal pigment epithelium cells
• retinal progenitor cells

• Humans
• Retinal Pigment Epithelium/metabolism
• Proteomics
• Oleic Acid/metabolism
• Extracellular Vesicles/metabolism
• Human Embryonic Stem Cells/metabolism
• Organoids/metabolism
• Lipid Metabolism

• 31930068 National Natural Science Foundation of China
• 82000945 National Natural Science Foundation of China
• 2021YFA1101203 National Key Research and Development Program of China
• 2018YFA0107302 National Key Research and Development Program of China
• National Natural Science Foundation of China
• National Key Research and Development Program of China

• Müller cell
• mammals
• neural regeneration
• reprogramming
• retinal regeneration

• IκBα
• LncRNA
• NF-κB signaling
• cancer stem cell

• Female
• Humans
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• NF-kappa B/genetics
• NF-kappa B/metabolism
• NF-KappaB Inhibitor alpha/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Signal Transduction
• Neoplastic Stem Cells/metabolism

Hepatocellular carcinoma (HCC) is considered the second most deadly cancer worldwide. Due to the absence of early diagnostic markers and effective therapeutic approaches, distant metastasis and increasing recurrence rates are major difficulties in the clinical treatment of HCC. Further understanding of its pathogenesis has become an urgent goal in HCC research. Recently, abnormal expression of long noncoding RNAs (lncRNAs) was identified as a vital regulator involved in the initiation and development of HCC. Activation of the Wnt/β-catenin pathway has been reported to obviously impact cell proliferation, invasion, and migration of HCC. This article reviews specific interactions, significant mechanisms and molecules related to HCC initiation and progression to provide promising strategies for treatment.

• Wnt pathway
• biomarker
• hepatocellular carcinoma
• long noncoding RNA
• prognosis

• cross-species
• peripheral blood mononuclear cells
• single-cell RNA sequencing

• Animals
• Cats
• Columbidae/genetics
• Deer/genetics
• Genetic Heterogeneity
• Goats/genetics
• Haplorhini/genetics
• Humans
• Leukocytes, Mononuclear/cytology
• Mesocricetus/genetics
• Mice/genetics
• Rabbits
• Sequence Analysis, RNA/methods
• Sequence Analysis, RNA/statistics & numerical data
• Single-Cell Analysis/instrumentation
• Single-Cell Analysis/methods
• Single-Cell Analysis/statistics & numerical data
• Species Specificity
• Tigers/genetics
• Wolves/genetics
• Zebrafish/genetics

• #81771300 National Natural Science Foundation of China
• #81971140 National Natural Science Foundation of China
• 2020009 Norman Bethune Foundation
• #2020A1515010053 Natural Science Foundation of Guangdong Province
• National Natural Science Foundation of China
• Natural Science Foundation of Guangdong Province

• cancer stem cells
• cervical cancer

• Bioinformatics analysis
• Caco-2
• Gma-miR159a
• Soybean
• TCF7
• microRNAs

• Apoptosis
• Caco-2 Cells
• Cell Line
• Cell Proliferation
• Colonic Neoplasms/genetics
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/pathology
• Disease Progression
• Humans
• Intestinal Mucosa/cytology
• MicroRNAs/physiology
• RNA, Plant/physiology
• Glycine max/genetics
• T Cell Transcription Factor 1/genetics
• T Cell Transcription Factor 1/metabolism

Colorectal cancer, one of the most common tumors, is mainly fatal because of the occurrence of liver metastasis. Inositol hexaphosphate (IP6) and inositol (INS) were found, both, in vitro and in vivo to play an anti-tumor effect, whereas the combination of IP6 and INS was more effective than IP6 or INS alone.

The inhibitory effects of IP6, INS and the combination of IP6+INS on tumor progression and liver metastasis of colorectal cancer were investigated in an orthotopic transplantation model of colorectal cancer. The tumor-bearing mice were selected by in vivo bioluminescence imaging and were treated with IP6, INS, and IP6 combined with INS, respectively. All mice were sacrificed after 6 weeks of treatment. The cancer development and metastasis were compared among the groups. The expression of genes related to the Wnt/β-catenin in the model was analyzed.

The results demonstrated that liver metastasis was inhibited after treatment with IP6, INS, and IP6+INS. Compared to that of the M_G, survival period was extended, and tumor weight was lowered in IP6_G, INS_G, and IP6+INS_G. Besides, the liver metastatic area of mice in IP6+INS_G was relatively smaller than that in M_G, IP6_G, or INS_G. The results of RNA-seq analysis showed that the expressions of Wnt10b, Tcf7, and c-Myc were significantly downregulated in IP6+INS_G compared to that in M_G (P<0.05). Results of real-time PCR and Western blot showed that mRNA and protein expressions of β-catenin, Wnt10b, Tcf7, and c-Myc were significantly lower in IP6+INS_G compared to that in M_G (P<0.05).

IP6+INS was more effective in inhibiting liver metastasis of colorectal cancer than IP6 or INS alone. The better inhibition effect may be accomplished through regulating the mutation of Wnt/β-catenin signaling pathway by inhibiting Wnt10b, Tcf7, β-catenin, and c-Myc from abnormally high expression.

• Wnt/β-catenin signaling
• colorectal cancer
• inositol
• inositol hexaphosphate
• liver metastasis
• mouse model

• Alzheimer’s disease
• drug development
• embryonic stem cells
• induced pluripotent stem cells
• mesenchymal stem cells
• nerve regeneration
• neural regeneration
• neural stem cells
• neurodegenerative disorders
• stem cell therapy
• β-amyloid

• differentiation
• human-induced pluripotent stem cells
• neural lineage
• primitive neural stem cells

Stem cell therapy may replace lost photoreceptors and preserve residual photoreceptors during retinal degeneration (RD). Unfortunately, the degenerative microenvironment compromises the fate of grafted cells, demanding supplementary strategies for microenvironment regulation. Donor cells with both proper regeneration capability and intrinsic ability to improve microenvironment are highly desired. Here, we use cell surface markers (C-Kit⁺/SSEA4⁻) to effectively eliminate tumorigenic embryonic cells and enrich retinal progenitor cells (RPCs) from human embryonic stem cell (hESC)-derived retinal organoids, which, following subretinal transplantation into RD models of rats and mice, significantly improve vision and preserve the retinal structure. We characterize the pattern of integration and materials transfer following transplantation, which likely contribute to the rescued photoreceptors. Moreover, C-Kit⁺/SSEA4⁻ cells suppress microglial activation, gliosis and the production of inflammatory mediators, thereby providing a healthier host microenvironment for the grafted cells and delaying RD. Therefore, C-Kit⁺/SSEA4⁻ cells from hESC-derived retinal organoids are a promising therapeutic cell source.

Stem cell transplantation to treat retinal degeneration could be limited by the degenerative microenvironment. Here, the authors show that C-Kit⁺/SSEA4^– progenitor cells enriched from human embryonic stem cell derived retinal organoids protect retinal structure, suppress microglial activation, gliosis and inflammation.

• adverse event
• clinical translation
• evolution
• genetic stability
• pluripotent stem-cell
• safety
• stem cell
• stem cell therapy
• stem-cell research

Sight is a major sense for human and visual impairment profoundly affects quality of life, especially retinal degenerative diseases which are the leading cause of irreversible blindness worldwide. As for other neurodegenerative disorders, almost all retinal dystrophies are characterized by the specific loss of one or two cell types, such as retinal ganglion cells, photoreceptor cells, or retinal pigmented epithelial cells. This feature is a critical point when dealing with cell replacement strategies considering that the preservation of other cell types and retinal circuitry is a prerequisite. Retinal ganglion cells are particularly vulnerable to degenerative process and glaucoma, the most common optic neuropathy, is a frequent retinal dystrophy. Cell replacement has been proposed as a potential approach to take on the challenge of visual restoration, but its application to optic neuropathies is particularly challenging. Many obstacles need to be overcome before any clinical application. Beyond their survival and differentiation, engrafted cells have to reconnect with both upstream synaptic retinal cell partners and specific targets in the brain. To date, reconnection of retinal ganglion cells with distal central targets appears unrealistic since central nervous system is refractory to regenerative processes. Significant progress on the understanding of molecular mechanisms that prevent central nervous system regeneration offer hope to overcome this obstacle in the future. At the same time, emergence of reprogramming of human somatic cells into pluripotent stem cells has facilitated both the generation of new source of cells with therapeutic potential and the development of innovative methods for the generation of transplantable cells. In this review, we discuss the feasibility of stem cell-based strategies applied to retinal ganglion cells and optic nerve impairment. We present the different strategies for the generation, characterization and the delivery of transplantable retinal ganglion cells derived from pluripotent stem cells. The relevance of pluripotent stem cell-derived retinal organoid and retinal ganglion cells for disease modeling or drug screening will be also introduced in the context of optic neuropathies.

• cell transplantation
• disease modeling
• glaucoma
• human iPSCs
• retinal ganglion cells (RGCs)

• Ciliary body
• Ciliary marginal zone
• Development
• Eye neurogenesis
• Retina
• Retinal regeneration

• TCF7
• colorectal cancer
• invasion
• miR-6852
• proliferation

• CRC
• EMT
• LncTCF7
• TCF7
• Wnt/β-catenin

Retinitis pigmentosa is a common genetic disease that causes retinal degeneration and blindness for which there is currently no curable treatment available. Vision preservation was observed in retinitis pigmentosa animal models after retinal stem cell transplantation. However, long-term safety studies and visual assessment have not been thoroughly tested in retinitis pigmentosa patients.

In our pre-clinical study, purified human fetal-derived retinal progenitor cells (RPCs) were transplanted into the diseased retina of Royal College of Surgeons (RCS) rats, a model of retinal degeneration. Based on these results, we conducted a phase I clinical trial to establish the safety and tolerability of transplantation of RPCs in eight patients with advanced retinitis pigmentosa. Patients were studied for 24 months.

After RPC transplantation in RCS rats, we observed moderate recovery of vision and maintenance of the outer nuclear layer thickness. Most importantly, we did not find tumor formation or immune rejection. In the retinis pigmentosa patients given RPC injections, we also did not observe immunological rejection or tumorigenesis when immunosuppressive agents were not administered. We observed a significant improvement in visual acuity (P < 0.05) in five patients and an increase in retinal sensitivity of pupillary responses in three of the eight patients between 2 and 6 months after the transplant, but this improvement did not appear by 12 months.

Our study for the first time confirmed the long-term safety and feasibility of vision repair by stem cell therapy in patients blinded by retinitis pigmentosa.

WHO Trial Registration, ChiCTR-TNRC-08000193. Retrospectively registered on 5 December 2008.

The online version of this article (doi:10.1186/s13287-017-0661-8) contains supplementary material, which is available to authorized users.

• Cell transplantation
• Progenitor cell
• Retina
• Retinitis pigmentosa
• Visual improvement

• Lineage tracing
• Progenitor cells
• Retina
• c-Kit

• Aging/physiology
• Animals
• Animals, Newborn
• Cell Lineage/drug effects
• Cell Separation
• Ependymoglial Cells/cytology
• Ependymoglial Cells/drug effects
• Ependymoglial Cells/metabolism
• Green Fluorescent Proteins/metabolism
• Mice
• Multipotent Stem Cells/cytology
• Multipotent Stem Cells/drug effects
• Multipotent Stem Cells/metabolism
• Neurons/cytology
• Neurons/drug effects
• Neurons/metabolism
• Proto-Oncogene Proteins c-kit/metabolism
• Retina/cytology
• Stem Cells/cytology
• Stem Cells/drug effects
• Stem Cells/metabolism
• Tamoxifen/pharmacology
• Time Factors

• P01 HL108801 NHLBI NIH HHS
• R01 HL102897 NHLBI NIH HHS
• P01 HL092868 NHLBI NIH HHS

• Wnt/β-catenin
• apoptosis
• cell cycle
• kallikrein-related peptidase 4
• oral squamous cell carcinoma
• proliferation

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.

• Differentiation
• Flow cytometry
• Human pluripotent stem cell
• Nanoparticle
• SERS assay

Alzheimer's disease (AD) is the most common cause of dementia in those over the age of 65. While a numerous of disease-causing genes and risk factors have been identified, the exact etiological mechanisms of AD are not yet completely understood, due to the inability to test theoretical hypotheses on non-postmortem and patient-specific research systems. The use of recently developed and optimized induced pluripotent stem cells (iPSCs) technology may provide a promising platform to create reliable models, not only for better understanding the etiopathological process of AD, but also for efficient anti-AD drugs screening. More importantly, human-sourced iPSCs may also provide a beneficial tool for cell-replacement therapy against AD. Although considerable progress has been achieved, a number of key challenges still require to be addressed in iPSCs research, including the identification of robust disease phenotypes in AD modeling and the clinical availabilities of iPSCs-based cell-replacement therapy in human. In this review, we highlight recent progresses of iPSCs research and discuss the translational challenges of AD patients-derived iPSCs in disease modeling and cell-replacement therapy.

• Alzheimer’s disease
• Cell-replacement therapy
• Disease modeling
• Drugs screening
• Induced pluripotent stem cells

Hepatic cell therapy has become a viable alternative to liver transplantation for life-threatening liver diseases. However, the supply of human hepatocytes is limited due to the shortage of suitable donor organs required to isolate high-quality cells. Human pluripotent stem cells reflect a potential renewable source for generating functional hepatocytes. However, most differentiation protocols use undefined matrices or factors of animal origin; as such, the resulting hepatocytes are not Good Manufacturing Practice compliant. Moreover, the preclinical studies employed to assess safety and function of human embryonic stem cell (hESC)-derived hepatocytes are generally limited to immunodeficient mice. In the present study, we evaluate the generation of hepatocytes under defined conditions using a European hESC line (VAL9) which was derived under animal-free conditions. The function capacity of VAL9-derived hepatocytes was assessed by transplantation into mice with acetaminophen-induced acute liver failure, a clinically relevant model.

We developed a protocol that successfully differentiates hESCs into bipotent hepatic progenitors under defined conditions, without the use of chromatin modifiers such as dimethyl sulphoxide. These progenitors can be cryopreserved and are able to generate both committed precursors of cholangiocytes and neonate-like hepatocytes.

Thirty days post-differentiation, hESCs expressed hepatocyte-specific markers such as asialoglycoprotein receptor and hepatic nuclear factors including HNF4α. The cells exhibited properties of mature hepatocytes such as urea secretion and UGT1A1 and cytochrome P450 activities. When transplanted into mice with acetaminophen-induced acute liver failure, a model of liver damage, the VAL9-derived hepatocytes efficiently engrafted and proliferated, repopulating up to 10 % of the liver. In these transplanted livers, we observed a significant decrease of liver transaminases and found no evidence of tumourigenicity. Thus, VAL9-derived hepatocytes were able to rescue hepatic function in acetaminophen-treated animals.

Our study reveals an efficient protocol for differentiating VAL9 hESCs to neonatal hepatocytes which are then able to repopulate livers in vivo without tumour induction. The human hepatocytes are able to rescue liver function in mice with acetaminophen-induced acute toxicity. These results provide proof-of-concept that replacement therapies using hESC-derived hepatocytes are effective for treating liver diseases.

The online version of this article (doi:10.1186/s13287-015-0227-6) contains supplementary material, which is available to authorized users.

• rat embryonic stem cell
• degenerative retinal diseases
• retinal progenitor cell (rpc)
• transplantation
• royal college of surgeons (rcs) rat

• Animals
• Antigens, Differentiation/metabolism
• Cell Differentiation/genetics
• Cell Movement
• Cell Survival
• Cells, Cultured
• Embryonic Stem Cells/cytology
• Embryonic Stem Cells/transplantation
• Gene Expression Profiling
• Gene Targeting
• In Vitro Techniques
• Neurons/cytology
• Rats
• Rats, Sprague-Dawley
• Retina/cytology
• Retina/surgery
• Retinal Degeneration/surgery
• Stem Cell Transplantation
• Stem Cells/cytology
• Stem Cells/metabolism
• Vision, Ocular

• DNA methylation
• epigenetic regulation
• head and neck cancer
• microRNA
• signaling transduction
• β-catenin

The wingless-type MMTV integration site (Wnt) signaling is a group of signal transduction pathways. In canonical Wnt pathway, Wnt ligands bind to low-density lipoprotein receptor-related protein 5 or 6 (LRP5 or LRP6), resulting in phosphorylation and activation of the receptor. We hypothesize that canonical Wnt pathway plays a role in the retinal lesion of age-related macular degeneration (AMD), a leading cause of irreversible central visual loss in elderly.

We examined LRP6 phosphorylation and Wnt signaling cascade in human retinal sections and plasma kallistatin, an endogenous inhibitor of the Wnt pathway in AMD patients and non-AMD subjects. We also used the Ccl2^−/−/Cx3cr1^−/−/rd8 and Ccl2^−/−/Cx3cr1^gfp/gfp mouse models with AMD-like retinal degeneration to further explore the involvement of Wnt signaling activation in the retinal lesions in those models and to preclinically evaluate the role of Wnt signaling suppression as a potential therapeutic option for AMD.

We found higher levels of LRP6 (a key Wnt signaling receptor) protein phosphorylation and transcripts of the Wnt pathway-targeted genes, as well as higher beta-catenin protein in AMD macula compared to controls. Kallistatin was decreased in the plasma of AMD patients. Retinal non-phosphorylated-β-catenin and phosphorylated-LRP6 were higher in Ccl2^−/−/Cx3cr1^−/−/rd8 mice than that in wild type. Intravitreal administration of an anti-LRP6 antibody slowed the progression of retinal lesions in Ccl2^−/−/Cx3cr1^−/−/rd8 and Ccl2^−/−/Cx3cr1^gfp/gfp mice. Electroretinography of treated eyes exhibited larger amplitudes compared to controls in both mouse models. A2E, a retinoid byproduct associated with AMD was lower in the treated eyes of Ccl2^−/−/Cx3cr1^−/−/rd8 mice. Anti-LRP6 also suppressed the expression of Tnf-α and Icam-1 in Ccl2^−/−/Cx3cr1^−/−/rd8 retinas.

Wnt signaling may be disturbed in AMD patients, which could contribute to the retinal inflammation and increased A2E levels found in AMD. Aberrant activation of canonical Wnt signaling might also contribute to the focal retinal degenerative lesions of mouse models with Ccl2 and Cx3cr1 deficiency, and intravitreal administration of anti-LRP6 antibody could be beneficial by deactivating the canonical Wnt pathway.

The online version of this article (doi:10.1186/s12967-015-0683-x) contains supplementary material, which is available to authorized users.

The cornea is essential for normal vision by maintaining transparency for light transmission. Limbal stem cells, which reside in the corneal periphery, contribute to the homeostasis of the corneal epithelium. Any damage or disease affecting the function of these cells may result in limbal stem cell deficiency (LSCD). The condition may result in both severe pain and blindness. Transplantation of ex vivo cultured cells onto the cornea is most often an effective therapeutic strategy for LSCD. The use of ex vivo cultured limbal epithelial cells (LEC), oral mucosal epithelial cells, and conjunctival epithelial cells to treat LSCD has been explored in humans. The present review focuses on the current state of knowledge of the many other cell-based therapies of LSCD that have so far exclusively been explored in animal models as there is currently no consensus on the best cell type for treating LSCD. Major findings of all these studies with special emphasis on substrates for culture and transplantation are systematically presented and discussed. Among the many potential cell types that still have not been used clinically, we conclude that two easily accessible autologous sources, epidermal stem cells and hair follicle-derived stem cells, are particularly strong candidates for future clinical trials.

• biomaterials
• cornea
• ex vivo cultivation
• limbal stem cell deficiency
• ocular surface disease
• transplantation

The relevance of retinal diseases, both in society’s economy and in the quality of people’s life who suffer with them, has made stem cell therapy an interesting topic for research. Embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adipose derived mesenchymal stem cells (ADMSCs) are the focus in current endeavors as a source of different retinal cells, such as photoreceptors and retinal pigment epithelial cells. The aim is to apply them for cell replacement as an option for treating retinal diseases which so far are untreatable in their advanced stage. ESCs, despite the great potential for differentiation, have the dangerous risk of teratoma formation as well as ethical issues, which must be resolved before starting a clinical trial. iPSCs, like ESCs, are able to differentiate in to several types of retinal cells. However, the process to get them for personalized cell therapy has a high cost in terms of time and money. Researchers are working to resolve this since iPSCs seem to be a realistic option for treating retinal diseases. ADMSCs have the advantage that the procedures to obtain them are easier. Despite advancements in stem cell application, there are still several challenges that need to be overcome before transferring the research results to clinical application. This paper reviews recent research achievements of the applications of these three types of stem cells as well as clinical trials currently based on them.

• Retina
• Adipose derived mesenchymal stem cells
• Embryonic stem cells
• Induced pluripotent stem cells
• Cell therapy

• Human pluripotent stem cells
• Metabolism
• NAD
• Salvage pathway
• Selective toxicity

• Cell Culture Techniques
• Cell Differentiation/drug effects
• Cytokines/antagonists & inhibitors
• Humans
• NAD/antagonists & inhibitors
• NAD/metabolism
• Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors
• Pluripotent Stem Cells/cytology
• Pluripotent Stem Cells/drug effects
• Pyridines/pharmacology
• Signal Transduction/drug effects
• Small Molecule Libraries/pharmacology

• GM080202 NIGMS NIH HHS
• R01 AI044458 NIAID NIH HHS
• R01 DK052194 NIDDK NIH HHS
• R01 HL058012 NHLBI NIH HHS
• R01HL58012 NHLBI NIH HHS
• R01DK44458 NIDDK NIH HHS
• T32 GM080202 NIGMS NIH HHS
• R00 HL094708 NHLBI NIH HHS
• R01DK52194 NIDDK NIH HHS
• 4R00HL094708 NHLBI NIH HHS

Eye development in vertebrates relies on the critical regulation of SOX2 expression. Humans with mutations in SOX2 often suffer from eye defects including anophthalmia (no eye) and microphthalmia (small eye). In mice, deletion of Sox2 in optic cup progenitor cells results in loss of neural competence and cell fate conversion of the neural retina to a non-neurogenic fate, specifically the acquisition of fate associated with progenitors of the ciliary epithelium. This fate is also promoted with constitutive expression of stabilized β-Catenin in the optic cup, where the WNT pathway is up-regulated. We addressed whether SOX2 co-ordinates the neurogenic boundary of the retina through modulating the WNT/β-Catenin pathway by using a genetic approach in the mouse.

Upon deletion of Sox2 in the optic cup, response to WNT signaling was expanded, correlating with loss of neural competence, cell fate conversion of the neural retina to ciliary epithelium primordium and, in addition, increased cell cycle time of optic cup progenitors. Removal of Ctnnb1 rescued the cell fate conversion; however, the loss of neural competence and the proliferation defect resulting from lack of SOX2 were not overcome. Lastly, central Sox2-deficient optic cup progenitor cells exhibited WNT-independent up-regulation of D-type Cyclins.

We propose two distinct roles for SOX2 in the developing retina. Our findings suggest that SOX2 antagonizes the WNT pathway to maintain a neurogenic fate and, in contrast, regulates cycling of optic cup progenitors in a WNT-independent manner. Given that WNT signaling acting upstream of SOX2 has been implicated in the tumorigenicity of embryonic stem cell-derived retinal progenitor cells, our results distinguish the endogenous role of WNT signaling in early optic cup patterning and support a WNT-independent role for SOX2 in maintaining retinal progenitor cell proliferation.

The online version of this article (doi:10.1186/1749-8104-9-27) contains supplementary material, which is available to authorized users.

• Muller glia
• Neuroprotection
• Retina
• Stat3
• Wnt

• Animals
• Cell Survival/drug effects
• Disease Models, Animal
• Ependymoglial Cells/drug effects
• Ependymoglial Cells/metabolism
• Female
• Male
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents/pharmacology
• Photoreceptor Cells/drug effects
• Photoreceptor Cells/metabolism
• Retinal Degeneration/metabolism
• STAT3 Transcription Factor/metabolism
• Wnt Signaling Pathway/drug effects
• Wnt3A Protein/metabolism
• Wnt3A Protein/pharmacology

• P30 EY014801 NEI NIH HHS
• R01 EY017837 NEI NIH HHS
• 3R01EY017837-03S1 NEI NIH HHS
• P30EY014801 NEI NIH HHS

• Beta-catenin (B-catenin)
• Epithelial-Mesenchymal Transition (EMT)
• Gene Expression
• MicroRNA (miRNA)
• Paired-like Homeodomain Transcription Factor 2 (PITX2)
• Reprogramming

• Amelogenin/genetics
• Amelogenin/metabolism
• Animals
• Cell Differentiation/physiology
• Epithelial Cells/cytology
• Epithelial Cells/metabolism
• Homeodomain Proteins/genetics
• Homeodomain Proteins/metabolism
• Humans
• Incisor/cytology
• Incisor/metabolism
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mice
• Mice, Transgenic
• MicroRNAs/genetics
• MicroRNAs/metabolism
• SOXB1 Transcription Factors/genetics
• SOXB1 Transcription Factors/metabolism
• Transcription Factors/genetics
• Transcription Factors/metabolism
• beta Catenin/genetics
• beta Catenin/metabolism
• Homeobox Protein PITX2

• R01 DE013941 NIDCR NIH HHS
• DE13941 NIDCR NIH HHS