RARα和RARγ相互控制发育中唾液腺的K5+祖细胞扩增。

IF 1.6 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Organogenesis Pub Date : 2017-10-02 Epub Date: 2017-09-21 DOI:10.1080/15476278.2017.1358336
Kara A DeSantis, Adam R Stabell, Danielle C Spitzer, Kevin J O'Keefe, Deirdre A Nelson, Melinda Larsen
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引用次数: 9

摘要

了解器官形成过程中基底祖细胞群受控扩增和分化的机制对于开发有针对性的再生疗法至关重要。由于唾液腺中细胞角蛋白5阳性(K5+)的基底上皮细胞群受视黄酸信号调控,我们研究了视黄酸受体(RAR)同工酶特异性信号如何在唾液腺器官发生过程中影响K5+细胞群,以确定可用于未来再生疗法的RAR同工酶特异性机制。在这项研究中,我们利用RAR同工酶特异性抑制剂和激动剂与小鼠下颌下腺唾液腺器官外植体进行了研究。我们确定 RARα 和 RARγ 对 K5+ 细胞周期进展和细胞分布具有相反的作用。RARα 对整个器官外植体和离体上皮原基中的 K5+ 细胞都有负向调节作用。与此相反,RARγ对K5+细胞的积极维持是必要的,但并不充分,因为单独激动RARγ并不能显著扩大K5+细胞的数量。虽然众所周知视黄醇能刺激分化,但 K5 水平与分化的导管细胞角蛋白并不成反比。相反,RARα激动和RARγ抑制与K5的减少相对应,会导致管腔过早形成,如prominin-1所示。通过系谱追踪,我们证明 K5+ 细胞有能力变成 prominin-1+ 细胞。我们的结论是,RARα和RARγ以细胞周期依赖的方式相互控制发育中的颌下腺唾液上皮内源性K5+祖细胞,控制管腔化,而不依赖于角质化分化。基于这些数据,对于寻求扩大 K5+祖细胞库的再生疗法来说,靶向 RARα 的同工酶抑制剂可能比泛 RAR 抑制剂更有效:RARα和RARγ以细胞周期依赖的方式相互控制发育中的颌下腺唾液上皮中K5+祖细胞的增殖和分布,同时调节腔化,而不依赖于角质化分化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

RARα and RARγ reciprocally control K5<sup>+</sup> progenitor cell expansion in developing salivary glands.

RARα and RARγ reciprocally control K5<sup>+</sup> progenitor cell expansion in developing salivary glands.

RARα and RARγ reciprocally control K5<sup>+</sup> progenitor cell expansion in developing salivary glands.

RARα and RARγ reciprocally control K5+ progenitor cell expansion in developing salivary glands.

Understanding the mechanisms of controlled expansion and differentiation of basal progenitor cell populations during organogenesis is essential for developing targeted regenerative therapies. Since the cytokeratin 5-positive (K5+) basal epithelial cell population in the salivary gland is regulated by retinoic acid signaling, we interrogated how isoform-specific retinoic acid receptor (RAR) signaling impacts the K5+ cell population during salivary gland organogenesis to identify RAR isoform-specific mechanisms that could be exploited in future regenerative therapies. In this study, we utilized RAR isoform-specific inhibitors and agonists with murine submandibular salivary gland organ explants. We determined that RARα and RARγ have opposing effects on K5+ cell cycle progression and cell distribution. RARα negatively regulates K5+ cells in both whole organ explants and in isolated epithelial rudiments. In contrast, RARγ is necessary but not sufficient to positively maintain K5+ cells, as agonism of RARγ alone failed to significantly expand the population. Although retinoids are known to stimulate differentiation, K5 levels were not inversely correlated with differentiated ductal cytokeratins. Instead, RARα agonism and RARγ inhibition, corresponding with reduced K5, resulted in premature lumenization, as marked by prominin-1. With lineage tracing, we demonstrated that K5+ cells have the capacity to become prominin-1+ cells. We conclude that RARα and RARγ reciprocally control K5+ progenitor cells endogenously in the developing submandibular salivary epithelium, in a cell cycle-dependent manner, controlling lumenization independently of keratinizing differentiation. Based on these data, isoform-specific targeting RARα may be more effective than pan-RAR inhibitors for regenerative therapies that seek to expand the K5+ progenitor cell pool.

Summary statement: RARα and RARγ reciprocally control K5+ progenitor cell proliferation and distribution in the developing submandibular salivary epithelium in a cell cycle-dependent manner while regulating lumenization independently of keratinizing differentiation.

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来源期刊
Organogenesis
Organogenesis BIOCHEMISTRY & MOLECULAR BIOLOGY-DEVELOPMENTAL BIOLOGY
CiteScore
4.10
自引率
4.30%
发文量
6
审稿时长
>12 weeks
期刊介绍: Organogenesis is a peer-reviewed journal, available in print and online, that publishes significant advances on all aspects of organ development. The journal covers organogenesis in all multi-cellular organisms and also includes research into tissue engineering, artificial organs and organ substitutes. The overriding criteria for publication in Organogenesis are originality, scientific merit and general interest. The audience of the journal consists primarily of researchers and advanced students of anatomy, developmental biology and tissue engineering. The emphasis of the journal is on experimental papers (full-length and brief communications), but it will also publish reviews, hypotheses and commentaries. The Editors encourage the submission of addenda, which are essentially auto-commentaries on significant research recently published elsewhere with additional insights, new interpretations or speculations on a relevant topic. If you have interesting data or an original hypothesis about organ development or artificial organs, please send a pre-submission inquiry to the Editor-in-Chief. You will normally receive a reply within days. All manuscripts will be subjected to peer review, and accepted manuscripts will be posted to the electronic site of the journal immediately and will appear in print at the earliest opportunity thereafter.
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