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Trigeminal nerve-derived substance P regulates limbal stem cells by the PI3K-AKT pathway.

ABSTRACT: Trigeminal nerve-derived substance P (SP), a widespread neuropeptide, is known to maintain the corneal epithelial homeostasis and promote the closure of wound healing. Using comprehensive in vivo and in vitro assays and RNA-sequencing analysis, we aimed to unveil the positive effects of SP on the biological characteristics of limbal stem cells (LSCs) and the underlying mechanism. SP enhanced the proliferation and stemness of LSCs in vitro. Correspondingly, it rescued corneal defects, corneal sensitivity, and the expression of LSC-positive markers in a neurotrophic keratopathy (NK) mouse model in vivo. Topical injection of a neurokinin-1 receptor (NK1R) antagonist caused similar pathological changes as in corneal denervated mice and attenuated LSC-positive markers levels. Mechanistically, we revealed that SP regulated LSCs functions by modulating the PI3K-AKT pathway. Our findings showed that the trigeminal nerve regulates LSCs by releasing SP, which may provide new insights into the regulation of LSCs' fate and stem cell therapy.

SUBMITTER: Xu P

PROVIDER: S-EPMC10176256 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Trigeminal nerve-derived substance P regulates limbal stem cells by the PI3K-AKT pathway.

Xu Peipei P Lin Xiongshi X Dong Xing X Liu Ying Y Wang Zhichong Z Wang Shuangyong S

iScience 20230418 5

Trigeminal nerve-derived substance P (SP), a widespread neuropeptide, is known to maintain the corneal epithelial homeostasis and promote the closure of wound healing. Using comprehensive in vivo and in vitro assays and RNA-sequencing analysis, we aimed to unveil the positive effects of SP on the biological characteristics of limbal stem cells (LSCs) and the underlying mechanism. SP enhanced the proliferation and stemness of LSCs in vitro. Correspondingly, it rescued corneal ...[more]

PMID: 37187698

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Project description:BackgroundTranscription factor 7-like 2 (TCF7L2), which previously known as TCF-4, is a major form of transcription factor involved in the downstream WNT signaling and exhibits the strongest association to diabetes susceptibility. Although we still do not know mechanistically how TCF7L2 exerts its physiological functions on pancreatic endocrine cells, it had been suggested that TCF7L2 may directly affect β-cell function by regulating the activation of PI3K/AKT signaling pathway.MethodsMIN6 cells were transfected with TCF7L2 knockdown virus or lenti-TCF7L2 virus for 48 h to evaluate the contribution of TCF7L2 to the PI3K/AKT signaling pathway and pancreatic β-cell function. This was confirmed by measuring the expression of PI3K p85 and p-Akt by western blotting and insulin secretion by enzyme-linked immunosorbent assay (ELISA), respectively. Chromatin immunoprecipitation (ChIP) and polymerase chain reaction (PCR) experiments were performed to explore the genomic distribution of TCF7L2-binding sites in the promoter of PIK3R1, the affinity between which was analyzed by the luciferase reporter assay.ResultsIn the present study, we strikingly identified that TCF7L2 could profoundly inhibit the expression of PIK3R1 gene and its encoding protein PI3K p85, which then could lead to the activation of PI3K/AKT signaling and stimulate insulin secretion in pancreatic β-cells. However, the integrity and stability of evolutionarily conserved TCF7L2-binding motif plays a very crucial role in the binding events between transcription factor TCF7L2 and its candidate target genes. We also found that the affinity of TCF7L2 to the promoter region of PIK3R1 alters upon the specific binding sites, which further provides statistical validation to the necessity of TCF7L2-binding motif.ConclusionsThis study demonstrated that TCF7L2 is closely bound to the specific binding regions of PIK3R1 promoter and prominently controls the transcription of its encoding protein p85, which further affects the activation of PI3K/AKT signaling pathway and insulin secretion.

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Trigeminal nerve-derived substance P regulates limbal stem cells by the PI3K-AKT pathway.

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Trigeminal nerve-derived substance P regulates limbal stem cells by the PI3K-AKT pathway.

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