Role of VIP and Sonic Hedgehog Signaling Pathways in Mediating Epithelial Wound Healing, Sensory Nerve Regeneration, and Their Defects in Diabetic Corneas

Diabetic Keratopathy, a sight-threatening corneal disease, comprises several symptomatic conditions including delayed epithelial wound healing, recurrent erosions, and sensory nerve (SN) neuropathy. We investigated the role of neuropeptides in mediating corneal wound healing, including epithelial wound closure and SN regeneration. Denervation by Resiniferatoxin severely impaired corneal wound healing and markedly up-regulated pro-inflammatory gene expression. Exogenous neuropeptides CGRP, SP, and VIP partially reversed Resiniferatoxin’s effects, with VIP specifically inducing IL-10 expression. Hence, we focused on VIP and observed that wounding induced VIP and VIPR1 expression in normal (NL), but not diabetic (DM) mouse corneas. Targeting VIPR1 in <em>NL</em> corneas attenuated corneal wound healing, dampened wound-induced expression of neurotrophic factors, and exacerbated inflammatory responses while exogenous VIP had the opposite effects in DM corneas. Remarkably, wounding and diabetes also affected the expression of Sonic Hedgehog (SHH) in a VIP-dependent manner. Downregulating SHH expression in NL corneas decreased, while exogenous SHH in DM corneas increased the rates of corneal wound healing. Furthermore, inhibition of SHH signaling dampened VIP-promoted corneal wound healing. We conclude that VIP regulates epithelial wound he<a></a><a>aling, inflammatory response, and nerve regeneration in the corneas in a</a> SHH-dependent manner, suggesting a therapeutic potential for these molecules in treating diabetic keratopathy.

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Role of VIP and Sonic Hedgehog signaling pathways in mediating epithelial wound healing, sensory nerve regeneration and their defects in diabetic corneas

10.2337/figshare.12168084.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Yangyang Zhang ◽

Nan Gao ◽

Lin Wu ◽

Patrick S. Y. Lee ◽

...

Keyword(s):

Wound Healing ◽

Nerve Regeneration ◽

Sonic Hedgehog ◽

Sensory Nerve ◽

Dependent Manner ◽

Corneal Wound Healing ◽

Epithelial Wound Healing ◽

Corneal Wound ◽

Diabetic Keratopathy

Diabetic Keratopathy, a sight-threatening corneal disease, comprises several symptomatic conditions including delayed epithelial wound healing, recurrent erosions, and sensory nerve (SN) neuropathy. We investigated the role of neuropeptides in mediating corneal wound healing, including epithelial wound closure and SN regeneration. Denervation by Resiniferatoxin severely impaired corneal wound healing and markedly up-regulated pro-inflammatory gene expression. Exogenous neuropeptides CGRP, SP, and VIP partially reversed Resiniferatoxin’s effects, with VIP specifically inducing IL-10 expression. Hence, we focused on VIP and observed that wounding induced VIP and VIPR1 expression in normal (NL), but not diabetic (DM) mouse corneas. Targeting VIPR1 in <em>NL</em> corneas attenuated corneal wound healing, dampened wound-induced expression of neurotrophic factors, and exacerbated inflammatory responses while exogenous VIP had the opposite effects in DM corneas. Remarkably, wounding and diabetes also affected the expression of Sonic Hedgehog (SHH) in a VIP-dependent manner. Downregulating SHH expression in NL corneas decreased, while exogenous SHH in DM corneas increased the rates of corneal wound healing. Furthermore, inhibition of SHH signaling dampened VIP-promoted corneal wound healing. We conclude that VIP regulates epithelial wound he<a></a><a>aling, inflammatory response, and nerve regeneration in the corneas in a</a> SHH-dependent manner, suggesting a therapeutic potential for these molecules in treating diabetic keratopathy.

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A critical role of autocrine sonic hedgehog signaling in human CD138+ myeloma cell survival and drug resistance

Blood ◽

10.1182/blood-2014-03-557298 ◽

2014 ◽

Vol 124 (13) ◽

pp. 2061-2071 ◽

Cited By ~ 48

Author(s):

Zhiqiang Liu ◽

Jingda Xu ◽

Jin He ◽

Yuhuan Zheng ◽

Haiyan Li ◽

...

Keyword(s):

Drug Resistance ◽

Cell Survival ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Critical Role ◽

Myeloma Cell ◽

Sonic Hedgehog Signaling ◽

Key Points

Key Points CD138+ MM cells are a major source of SHH. Autocrine SHH enhances MM drug resistance.

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The role of the sonic hedgehog signaling pathway in early brain injury after experimental subarachnoid hemorrhage in rats

Neuroscience Letters ◽

10.1016/j.neulet.2013.07.042 ◽

2013 ◽

Vol 552 ◽

pp. 81-86 ◽

Cited By ~ 9

Author(s):

Tao Li ◽

Jie Zhang ◽

Rong-Yao Liu ◽

Zhi-Gang Lian ◽

Xiao-Lin Chen ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Early Brain Injury ◽

Hedgehog Signaling Pathway ◽

Sonic Hedgehog Signaling ◽

Experimental Subarachnoid Hemorrhage ◽

Sonic Hedgehog Signaling Pathway

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Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells

Cell Death and Disease ◽

10.1038/s41419-020-02956-2 ◽

2020 ◽

Vol 11 (9) ◽

Cited By ~ 1

Author(s):

Cheng Wei ◽

Yibin Pan ◽

Yinli Zhang ◽

Yongdong Dai ◽

Lingling Jiang ◽

...

Keyword(s):

Wound Healing ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Sonic Hedgehog Signaling ◽

Endometrial Stromal Cells ◽

Shh Pathway ◽

Intrauterine Adhesion ◽

Stromal Cell Line ◽

Pathway Inhibition ◽

The Impact

Abstract Autophagy can be dynamically induced in response to stresses and is an essential, ubiquitous intracellular recycling system that impacts the fate of damaged resident cells, thereby influencing wound healing. Endometrial fibrosis is a form of abnormal wound healing that causes intrauterine adhesion (IUA) and infertility. We previously demonstrated that overactivated sonic hedgehog (SHH) signaling exacerbated endometrial fibrosis, but the role of autophagy in this process is still unknown. Here, we report that impaired autophagy participates in SHH pathway-induced endometrial fibrosis. Endometrial stroma-myofibroblast transition accompanied by autophagy dysfunction was present in both endometrial biopsies of IUA patients and Amhr2cre/+R26-SmoM2+/− (AM2) transgenic mouse. Mechanistically, SHH pathway negatively regulated autophagy through pAKT-mTORC1 in a human endometrial stromal cell line (T-HESCs). Furthermore, SHH pathway-mediated fibrosis was partly counteracted by autophagy modulation in both T-HESCs and the murine IUA model. Specifically, the impact of SHH pathway inhibition (GANT61) was reversed by the pharmacological autophagy inhibitor chloroquine (CQ) or RNA interference of autophagy-related gene ATG5 or ATG7. Similar results were obtained from the murine IUA model treated with GANT61 and CQ. Moreover, promoting autophagy with rapamycin reduced fibrosis in the AM2 IUA model to baseline levels. In summary, defective autophagy is involved in SHH pathway-driven endometrial fibrosis, suggesting a potential novel molecular target for IUA treatment.

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