Sosnowski Paweł, Sass Piotr, Słonimska Paulina, Płatek Rafał, Kamińska Jolanta, Baczyński Keller Jakub, Mucha Piotr, Peszyńska-Sularz Grażyna, Czupryn Artur, Pikuła Michał, Piotrowski Arkadiusz, Janus Łukasz, Rodziewicz-Motowidło Sylwia, Skowron Piotr, Sachadyn Paweł
Laboratory for Regenerative Biotechnology, Gdańsk University of Technology, 80-233 Gdańsk, Poland.
Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdańsk, 80-308 Gdańsk, Poland.
Pharmaceuticals (Basel). 2022 May 16;15(5):610. doi: 10.3390/ph15050610.
The ear pinna is a complex tissue consisting of the dermis, cartilage, muscles, vessels, and nerves. Ear pinna healing is a model of regeneration in mammals. In some mammals, including rabbits, punch wounds in the ear pinna close spontaneously; in common-use laboratory mice, they remain for life. Agents inducing ear pinna healing are potential regenerative drugs. We tested the effects of selected bioactive agents on 2 mm ear pinna wound closure in BALB/c mice. Our previous research demonstrated that a DNA methyltransferase inhibitor, zebularine, remarkably induced ear pinna regeneration. Although experiments with two other demethylating agents, RG108 and hydralazine, were unsuccessful, a histone deacetylase inhibitor, valproic acid, was another epigenetic agent found to increase ear hole closure. In addition, we identified a pro-regenerative activity of 4-ketoretinoic acid, a retinoic acid metabolite. Attempts to counteract the regenerative effects of the demethylating agent zebularine, with folates as methyl donors, failed. Surprisingly, a high dose of methionine, another methyl donor, promoted ear hole closure. Moreover, we showed that the regenerated areas of ear pinna were supplied with nerve fibre networks and blood vessels. The ear punch model proved helpful in testing the pro-regenerative activities of small-molecule compounds and observations of peripheral nerve regeneration.
耳廓是一种复杂的组织，由真皮、软骨、肌肉、血管和神经组成。耳廓愈合是哺乳动物再生的一个模型。在包括兔子在内的一些哺乳动物中，耳廓的打孔伤口会自发闭合；而在常用的实验室小鼠中，这些伤口会终生存在。诱导耳廓愈合的物质是潜在的再生药物。我们测试了选定的生物活性剂对BALB/c小鼠2毫米耳廓伤口闭合的影响。我们之前的研究表明，一种DNA甲基转移酶抑制剂——泽布替尼，能显著诱导耳廓再生。虽然使用另外两种去甲基化剂RG108和肼屈嗪的实验没有成功，但一种组蛋白脱乙酰酶抑制剂——丙戊酸，是另一种被发现能增加耳洞闭合的表观遗传剂。此外，我们还确定了视黄酸代谢物4-酮视黄酸的促再生活性。用叶酸作为甲基供体来对抗去甲基化剂泽布替尼的再生作用的尝试失败了。令人惊讶的是，另一种甲基供体高剂量甲硫氨酸促进了耳洞闭合。此外，我们还表明，再生的耳廓区域有神经纤维网络和血管供应。耳廓打孔模型被证明有助于测试小分子化合物的促再生活性以及观察周围神经再生。
