Reprogramming of epidermal keratinocytes by PITX1 transforms the cutaneous cellular landscape and promotes wound healing.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Andrew M Overmiller, Akihiko Uchiyama, Emma D Hope, Subhashree Nayak, Christopher G O'Neill, Kowser Hasneen, Yi-Wen Chen, Faiza Naz, Stefania Dell'Orso, Stephen R Brooks, Kan Jiang, Maria I Morasso
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Abstract

Cutaneous wound healing is a slow process that often terminates with permanent scarring while oral wounds, in contrast, regenerate damage faster. Unique molecular networks in epidermal and oral epithelial keratinocytes contribute to the tissue-specific response to wounding, but key factors that establish those networks and how the keratinocytes interact with their cellular environment remain to be elucidated. The transcription factor PITX1 is highly expressed in the oral epithelium but is undetectable in cutaneous keratinocytes. To delineate if PITX1 contributes to oral keratinocyte identity, cell-cell interactions, and the improved wound healing capabilities, we ectopically expressed PITX1 in the epidermis of murine skin. Using comparative analysis of murine skin and oral (buccal) mucosa with scRNA-seq and spatial transcriptomics, we found that PITX1 expression enhances epidermal keratinocyte migration, proliferation, and alters differentiation to a quasi-oral keratinocyte state. PITX1+ keratinocytes reprogram intercellular communication between skin-resident cells to mirror buccal tissue while also stimulating the influx of neutrophils that establish a pro-inflammatory environment. Furthermore, PITX1+ skin heals significantly faster than control skin via increased keratinocyte activation and migration and a tunable inflammatory environment. These results illustrate that PITX1 programs oral keratinocyte identity and cellular interactions while also revealing critical downstream networks that promote wound closure.

PITX1 对表皮角质细胞的重编程改变了皮肤细胞的结构,促进了伤口愈合。
皮肤伤口愈合是一个缓慢的过程,通常会留下永久性疤痕,而口腔伤口的损伤再生速度较快。表皮和口腔上皮角质细胞中独特的分子网络促成了组织对伤口的特异性反应,但建立这些网络的关键因素以及角质细胞如何与其细胞环境相互作用仍有待阐明。转录因子 PITX1 在口腔上皮细胞中高度表达,但在皮肤角质形成细胞中却检测不到。为了弄清 PITX1 是否有助于口腔角质形成细胞的特性、细胞与细胞之间的相互作用以及伤口愈合能力的提高,我们在小鼠皮肤表皮中异位表达了 PITX1。通过利用 scRNA-seq 和空间转录组学对小鼠皮肤和口腔(颊)粘膜进行比较分析,我们发现 PITX1 的表达增强了表皮角质形成细胞的迁移和增殖,并改变了分化为准口腔角质形成细胞的状态。PITX1+角质形成细胞重新规划了皮肤驻留细胞之间的细胞间交流,使之与口腔组织相一致,同时还刺激了中性粒细胞的涌入,从而建立了一种促炎环境。此外,通过增加角质形成细胞的活化和迁移以及可调的炎症环境,PITX1+ 皮肤的愈合速度明显快于对照组皮肤。这些结果表明,PITX1 可对口腔角质形成细胞身份和细胞相互作用进行编程,同时还揭示了促进伤口闭合的关键下游网络。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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