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

Kaplan, Nihal; Dong, Ying; Wang, Sijia; Yang, Wending; Park, Jong Kook; Wang, Junyi; Fiolek, Elaina; White, Bethany E. Perez; Chandel, Navdeep S.; Han, Pei; Lavker, Robert M.

doi:10.1096/fj.201901512r

Cited by 10 publications

(10 citation statements)

References 61 publications

(216 reference statements)

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“…Immortalized corneal epithelial cells, hTCEpi, were cultured in keratinocyte serum‐free media (Thermo Fisher Scientific, Waltham, MA, USA) as described before 35 . For siRNA knock‐down experiments, cells were transfected with 10 nM siRNA SMARTpools against ACE2 and nontarget control (GE Dharmacon, Colorado, USA) as previously described 33 . Two days after transfection, cells were treated with losartan (100μM) for 24 hours, and processed for total RNA isolation.…”

Section: Methodsmentioning

confidence: 99%

“…At the termination of the experiment, mouse whole eyes were fixed in 10% buffered formalin solution and paraffin embedded for histological analysis. H&E staining was conducted as described previously 33 and slides were imaged using an AxioVision Z1 fluorescence microscope system (Carl Zeiss, Oberkochen, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…35 For siRNA knock-down experiments, cells were transfected with 10 nM siRNA SMARTpools against ACE2 and nontarget control (GE Dharmacon, Colorado, USA) as previously described. 33 Two days after transfection, cells were treated with losartan (100μM) for 24 hours, and processed for total RNA isolation. Human monocytic THP-1-Dual cells (InvivoGen, San Diego, CA, USA) were cultured with RMPI 1640 with 10% heat inactivated FBS.…”

Section: Cell Culturementioning

confidence: 99%

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The ACE2‐deficient mouse: A model for a cytokine storm‐driven inflammation

et al. 2020

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Angiotensin converting enzyme 2 (ACE2) plays an important role in inflammation, which is attributable at least, in part, to the conversion of the pro-inflammatory angiotensin (Ang) II peptide into angiotensin 1-7 (Ang 1-7), a peptide which opposes the actions of AngII. ACE2 and AngII are present in many tissues but information on the cornea is lacking. We observed that mice deficient in the Ace2 gene (Ace2 −/−), developed a cloudy cornea phenotype as they aged. Haze occupied the central cornea, accompanied by corneal edema and neovascularization. In severe cases with marked chronic inflammation, a cell-fate switch from a transparent corneal epithelium to a keratinized, stratified squamous, psoriasiform-like epidermis was observed. The stroma contained a large number of CD11c, CD68, and CD3 positive cells. Corneal epithelial debridement experiments in young ACE2-deficient mice showed normal appearing corneas, devoid of haze. We hypothesized, however, that these mice are "primed" for a corneal inflammatory response, which once initiated, would persist. In vitro studies reveal that interleukins (IL-1a, IL-1b), chemokines (CCL2, CXCL8), and TNF-α, are all significantly elevated, resulting in a cytokine storm-like phenotype. This phenotype could be partially rescued by treatment with the AngII type 1 receptor (AT1R) antagonist, losartan, suggesting that the observed effect was mediated by AngII acting on its main receptor. Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes human ACE2 as the receptor for entry with subsequent downregulation of ACE2, corneal inflammation in Ace2 −/− mice may have a similar mechanism with that in COVID-19 patients. Thus the Ace2 −/− cornea, because of easy accessibility, may provide an attractive model to explore the molecular mechanisms, immunological changes, and treatment modalities in patients with COVID-19.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

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The ACE2‐deficient mouse: A model for a cytokine storm‐driven inflammation

et al. 2020

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“…Western blots were performed as described previously 37 . The following antibodies were used: glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) (Santa Cruz Biotechnology, Inc, Santa Cruz, CA, USA), Beclin 1, p‐p38 (Cell Signaling Technology, Danvers, MA, USA), and PBK (Proteintech, Rosemont, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

Autophagy plays a positive role in induction of epidermal proliferation

et al. 2020

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Autophagy is critical for mediating intrinsic and extrinsic cellular stress-related situations in tissues. 1-8 Upon stimulation (eg, starvation, UV radiation), this self-cannibalistic process starts with activation of the Beclin 1-containing class III phosphatidylinositol 3-kinase (PI3K-III) complex. This lipid kinase complex is required for recruitment of autophagyrelated gene (ATG) proteins and ultimately formation of LC3II, a mature form of LC3 protein, on the double membranes of autophagosomes. 9 Autophagosomes fuse with lysosomes to form autolysosomes, where degradation occurs.

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“…Western blots were performed as described previously 40 . The following antibodies were used: p‐ERK1/2, p‐EphA2 (S897), pY1068‐EGFR, pY845‐EGFR, EGFR (Cell Signaling Technologies, Danvers, MA, USA), Ephrin‐A1‐AF702 (R&D Systems), EphA2 (D7‐Life Technologies), Ephrin‐A3, GAPDH (Santa Cruz, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Eph signaling is regulated by miRNA‐210: Implications for corneal epithelial repair

et al. 2021

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A distinct boundary exists between the progenitor cells in the basal limbal epithelium and the more differentiated corneal epithelial basal cells. We have shown that reciprocal expression patterns of EphA2 and Ephrin-A1 are likely to contribute to normal limbal-corneal epithelial compartmentalization as well as play a role in response to injury. How this signaling axis is regulated remains unclear.We have demonstrated that microRNAs (miRNAs) play critical roles in corneal epithelial wound healing and several miRNAs (e.g. miR-210) have been predicted to target ephrins. Previous expression profiling experiments demonstrated that miR-210 is prominently expressed in corneal epithelial cells. RNA-seq data acquired from miR-210-depleted HCECs showed up-regulation of genes involved in cellular migration. In addition, miR-210 is decreased after corneal injury while EphA2 is increased. Moreover, antago-210-treated HCECs markedly enhanced wound closure in a scratch wound assay. Antago-210 treatment resulted in increased EphA2 protein levels as well as pS897-EphA2, the pro-migratory form of EphA2. As expected, Ephrin-A1 levels were reduced, while levels of a wellknown target of miR-210, Ephrin-A3, were increased by antago-210 treatment.The increase in migration with antago-210 could be inhibited by Ephrin-A1 overexpression, Ephrin-A1-Fc treatment or siRNA depletion of EphA2. However, depletion of Ephrin-A3 did not have effects on the antago-210-induced increase in migration. In addition, Ephrin-A1 overexpression and siEphA2 dampened EGFR signaling, which is increased by antago-210. Our data clearly demonstrate a link between miR-210 and EphA2/Ephrin-A1 signaling that regulates, in part, corneal epithelial migration. This interaction might potentially control the limbalcorneal epithelial boundary.

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

Cited by 10 publications

References 61 publications

The ACE2‐deficient mouse: A model for a cytokine storm‐driven inflammation

The ACE2‐deficient mouse: A model for a cytokine storm‐driven inflammation

Autophagy plays a positive role in induction of epidermal proliferation

Eph signaling is regulated by miRNA‐210: Implications for corneal epithelial repair

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