Limb regeneration in higher vertebrates: Developing a roadmap
Limb regeneration in higher vertebrates: Developing a roadmap
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DOI：
10.1002/ar.b.20082
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发表时间：
2005-11-01
期刊：
影响因子：
--
通讯作者：
Muneoka, Ken
中科院分区：
文献类型：
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作者：
Han, Manjong;Yang, Xiaodong;Muneoka, Ken
我们从制定诱导成年哺乳动物再生策略的角度回顾了对两栖动物肢体再生的了解。有尾目两栖动物肢体再生中最突出的是未分化细胞胚基的形成，这些细胞继续改造肢体。芽基与发育中的肢芽有许多共同的特性。因此，再生的生长阶段可以被认为是细胞再次经历发育，即再发育。鉴于我们对肢体发育的广泛了解，哺乳动物进入再发育阶段将是一个重大突破。芽基本身的形成代表了一个过渡阶段，其中肢体细胞通过去分化成为可以进行再发育的胚胎肢体祖细胞来对损伤做出反应。在此阶段，伤口快速闭合，然后肢体细胞去分化形成胚基。因此，再生过程可以分为伤口愈合/去分化阶段和再发育阶段，我们认为伤口愈合反应和获得发育调节程序（去分化）之间的界面是哺乳动物再生问题的核心。在有尾目两栖动物中，肢体的所有组织都可能发生去分化。然而，大量研究使我们将注意力集中在表皮、真皮和肌肉上，它们是再生的关键调节因子。在高等脊椎动物中，包括人类在内的哺乳动物的指尖具有再生能力，并提供了独特的哺乳动物再生模型。最近对小鼠进行的遗传学研究发现，Msx1 基因在导致指尖再生的损伤反应中发挥着关键作用。从两栖动物到哺乳动物的再生研究结果可以整合起来，制定哺乳动物再生路线图，其重点是了解去分化现象。
We review what is known about amphibian limb regeneration from the prospective of developing strategies for the induction of regeneration in adult mammals. Prominent in urodele amphibian limb regeneration is the formation of a blastema of undifferentiated cells that goes on to reform the limb. The blastema shares many properties with the developing limb bud; thus, the outgrowth phase of regeneration can be thought of as cells going through development again, i.e., redevelopment. Getting to a redevelopment phase in mammals would be a major breakthrough given our extensive understanding of limb development. The formation of the blastema itself represents a transition phase in which limb cells respond to injury by dedifferentiating to become embryonic limb progenitor cells that can undergo redevelopment. During this phase, rapid wound closure is followed by the dedifferentiation of limb cells to form the blastema. Thus, the regeneration process can be divided into a wound-healing/dedifferentiation phase and a redevelopment phase, and we propose that the interface between the wound-healing response and gaining access to developmentally regulated programs (dedifferentiation) lies at the heart of the regeneration problem in mammals. In urodele amphibians, dedifferentiation can occur in all of the tissues of the limb; however, numerous studies lead us to focus on the epidermis, the dermis, and muscle as key regulators of regeneration. Among higher vertebrates, the digit tip in mammals, including humans, is regeneration-competent and offers a unique mammalian model for regeneration. Recent genetic studies in mice identify the Msx1 gene as playing a critical role in the injury response leading to digit tip regeneration. The results from regeneration studies ranging from amphibians to mammals can be integrated to develop a roadmap for mammalian regeneration that has as its focus understanding the phenomenon of dedifferentiation.