microRNA-103/107 Family Regulates Multiple Epithelial Stem Cell Characteristics

Han, Pei; Park, Jong Kook; Katsnelson, Julia; Kaplan, Nihal; Yang, Wending; Getsios, Spiro; Lavker, Robert M.

doi:10.1002/stem.1962

Cited by 48 publications

(105 citation statements)

References 101 publications

(140 reference statements)

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“…Eyes from a cadaver donor were embedded in optimal cutting temperature compound and stored at −80°C until sectioning. Basal cells from limbal and corneal epithelia from 5‐|xm frozen sections were isolated and captured using a Palm laser capture system (Carl Zeiss, Oberkochen, Germany) as previously described (19, 29). Total cellular RNA from laser capture microdissection‐captured cells was isolated and purified with an miRNeasy kit (Qiagen, Valencia, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Within the cornea, several miRNAs are expressed preferentially in the corneal epithelium and have been shown to regulate lineage specification, cell migration, cell survival, differentiation, and glycogen storage (12–18). Recently, the miR‐103/107 family was demonstrated to be limbal epithelium‐enriched, regulating slow‐cycling, proliferative capacity, and cell‐cell communication, all characteristics of epithelial stem cells (19). As in other tissues, changes in corneal miRNA expression have been linked to pathology, such as wound healing [reviewed in Funari et al .…”

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confidence: 99%

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miR‐184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways

et al. 2016

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Corneal avascularity is critical for achieving transparency necessary for proper transmission of light to the lens and visual acuity. Although much is known about angiogenesis and angiostasis, the precise regulation of these processes in the cornea is unclear. MicroRNA (miR)-184, the most abundant corneal epithelial miRNA, has been suggested to function in corneal angiostasis by altering VEGF signaling; however, the mechanism(s) underlying this regulation have not been addressed. Using a combination of in vitro and in vivo assays to evaluate angiogenesis, we demonstrated that human limbal epithelial keratinocytes (HLEKs) engineered to overexpress miR-184 secreted lower amounts of angiogenic mitogens. Human dermal microvascular cells exposed to conditioned medium from miR-184-overexpressing HLEKs were less proliferative and failed to seal linear scratch wounds. The in vivo Matrigel plug assay showed that conditioned medium from miR-184-expressing HLEKs elicited a lesser degree of neovascularization compared with controls. We found that miR-184 directly targets and represses the proangiogenic factors, friend of Gata 2 (FOG2), platelet-derived growth factor (PDGF)-β, and phosphatidic acid phosphatase 2b (PPAP2B). FOG2 regulates VEGF expression, whereas PDGF-β and PPAP2B regulate Akt activity. By attenuating both VEGF and Akt signaling, miR-184 acts as a broad-spectrum negative regulator of corneal angiogenesis.-Park, J. K., Peng, H., Yang, W., Katsnelson, J., Volpert, O., Lavker, R. M. miR-184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

miR‐184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways

et al. 2016

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“…In the cornea, some miRNAs display topographical expression differences between central part, limbus, and adjacent conjunctiva (Xu, 2009; Karali et al, 2010; Saghizadeh et al, 2013a; Peng et al, 2015; Teng et al, 2015). Interestingly, several miRNAs with preferential limbal epithelial localization appear to play a role in delayed wound healing in diabetic corneas (Funari et al, 2013; Saghizadeh et al, 2013b; Winkler et al, 2014).…”

Section: Corneal Epithelial Wound Healingmentioning

confidence: 99%

Progress in corneal wound healing

Ljubimov

Saghizadeh

2015

Progress in Retinal and Eye Research

582

554

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Corneal wound healing is a complex process involving cell death, migration, proliferation, differentiation, and extracellular matrix remodeling. Many similarities are observed in the healing processes of corneal epithelial, stromal and endothelial cells, as well as cell-specific differences. Corneal epithelial healing largely depends on limbal stem cells and remodeling of the basement membrane. During stromal healing, keratocytes get transformed to motile and contractile myofibroblasts largely due to activation of transforming growth factor-β system. Endothelial cells heal mostly by migration and spreading, with cell proliferation playing a secondary role. In the last decade, many aspects of wound healing process in different parts of the cornea have been elucidated, and some new therapeutic approaches have emerged. The concept of limbal stem cells received rigorous experimental corroboration, with new markers uncovered and new treatment options including gene and microRNA therapy tested in experimental systems. Transplantation of limbal stem cell-enriched cultures for efficient re-epithelialization in stem cell deficiency and corneal injuries has become reality in clinical setting. Mediators and course of events during stromal healing have been detailed, and new treatment regimens including gene (decorin) and stem cell therapy for excessive healing have been designed. This is a very important advance given the popularity of various refractive surgeries entailing stromal wound healing. Successful surgical ways of replacing the diseased endothelium have been clinically tested, and new approaches to accelerate endothelial healing and suppress endothelial-mesenchymal transformation have been proposed including Rho kinase (ROCK) inhibitor eye drops and gene therapy to activate TGF-β inhibitor SMAD7. Promising new technologies with potential for corneal wound healing manipulation including microRNA, induced pluripotent stem cells to generate corneal epithelium, and nanocarriers for corneal drug delivery are discussed. Attention is also paid to problems in wound healing understanding and treatment, such as lack of specific epithelial stem cell markers, reliable identification of stem cells, efficient prevention of haze and stromal scar formation, lack of data on wound regulating microRNAs in keratocytes and endothelial cells, as well as virtual lack of targeted systems for drug and gene delivery to select corneal cells.

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“…26 The following antibodies were used: FIH-1, Grb2, tubulin, glyceraldehyde 3-phosphate dehydrogenase, Notch1, GADD45α, FLAG (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA), p63α, E-cad, STAT1, pY701-STAT1, Plectin1, HDAC1, (Cell Signaling Technology, Danvers, MA, USA), ASPP2 (Abcam, Cambridge, United Kingdom), and β-catenin (Sigma-Aldrich Corp., St Louis, MO, USA). 26 The following antibodies were used: FIH-1, Grb2, tubulin, glyceraldehyde 3-phosphate dehydrogenase, Notch1, GADD45α, FLAG (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA), p63α, E-cad, STAT1, pY701-STAT1, Plectin1, HDAC1, (Cell Signaling Technology, Danvers, MA, USA), ASPP2 (Abcam, Cambridge, United Kingdom), and β-catenin (Sigma-Aldrich Corp., St Louis, MO, USA).…”

Section: Western Blottingmentioning

confidence: 99%

FIH‐1 engages novel binding partners to positively influence epithelial proliferation via p63

et al. 2019

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Whereas much is known about the genes regulated by ΔNp63α in keratinocytes, how ΔNp63α is regulated is less clear. During studies with the hydroxylase, factor inhibiting hypoxia‐inducible factor 1 (FIH‐1), we observed increases in epidermal ΔNp63α expression along with proliferative capacity in a conditional FIH‐1 transgenic mouse. Conversely, loss of FIH‐1 in vivo and in vitro attenuated ΔNp63α expression. To elucidate the FIH‐1/p63 relationship, BioID proteomics assays identified FIH‐1 binding partners that had the potential to regulate p63 expression. FIH‐1 interacts with two previously unknown partners, Plectin1 and signal transducer and activator of transcription 1 (STAT1) leading to the regulation of ΔNp63α expression. Two known interactors of FIH‐1, apoptosis‐stimulating of P53 protein 2 (ASPP2) and histone deacetylase 1 (HDAC1), were also identified. Knockdown of ASPP2 upregulated ΔNp63α and reversed the decrease in ΔNp63α by FIH‐1 depletion. Additionally, FIH‐1 regulates growth arrest and DNA damage‐45 alpha (GADD45α), a negative regulator of ΔNp63α by interacting with HDAC1. GADD45α knockdown rescued reduction in ΔNp63α by FIH‐1 depletion. Collectively, our data reveal that FIH‐1 positively regulates ΔNp63α in keratinocytes via variety of signaling partners: (a) Plectin1/STAT1, (b) ASPP2, and (c) HDAC1/GADD45α signaling pathways.

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microRNA-103/107 Family Regulates Multiple Epithelial Stem Cell Characteristics

Cited by 48 publications

References 101 publications

miR‐184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways

miR‐184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways

Progress in corneal wound healing

FIH‐1 engages novel binding partners to positively influence epithelial proliferation via p63

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