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In nature, mechanical stress caused by various biotic and abiotic factors often results in partial or even complete loss of organs and tissues of living organisms. In response to injury, both plants and animals have the ability to repair tissues and regenerate organs. Sessile-growing plants are more susceptible to mechanical damage than animals. However, during the long process of evolution, plants have developed an amazing ability to cope with damage that is unparalleled by animals. First, in the face of ever-present and unpredictable mechanical damage, plants can quickly activate defense responses to avoid insect pests and wound infections. Second, in the face of varying degrees of mechanical damage, plants can easily repair tissues and regenerate organs and even entire organisms.

在自然界，由各种生物和非生物因子带来的机械胁迫常造成生命体器官和组织的部分甚至完全缺失。应对损伤，无论是植物还是动物均具备组织修复和器官再生的能力。与动物相比，固着生长的植物更容易遭受机械损伤。然而植物在长期的进化过程中形成了令人叹为观止的、动物不可比拟的应对损伤的能力。第一，面对无时不在、不可预期的机械损伤，植物能够快速激活防御反应以避免病虫侵害和伤口感染。第二，面对不同程度的机械损伤，植物能够轻松自如地进行组织修复和器官乃至整个生命体的再生。

Tomato is a classic model plant for studying plant injury responses. In this model system, Professor Clarence Ryan (1931-2007) discovered the systemic defense phenomenon of plants against mechanical damage and insect intrusion in 1972 (that is, after a plant is injured, it not only initiates defense responses at the injured site, but also throughout the plant's body, including The uninjured area initiates a defense response). In the early 1990s, Professor Ryan's research group discovered that systemin (the first small peptide hormone discovered in the plant kingdom) and jasmonic acid regulate the systemic defense response of plants through a common signaling pathway, thereby establishing the field of plant systemic defense. Basic working model.

番茄是研究植物受伤反应的经典模式植物。在这一模式系统中，Clarence Ryan教授（1931-2007）于1972年发现了植物对机械损伤和昆虫侵害的系统性防御现象（即植物受伤后不只在受伤部位启动防御反应，而且在植物全身包括未受伤部位启动防御反应）。上世纪90年代初，Ryan教授研究组发现系统素（植物界发现的第一个小肽激素）和茉莉酸通过共同的信号通路调控植物的系统性防御反应，从而建立了植物系统性防御领域的基本工作模型。

In contrast, little is known about the primary signals that trigger plant regeneration due to injury and their transduction mechanisms. It is well known that cell damage is the primary physical trigger that triggers the regeneration process in living organisms, whether plants or animals. Based on this, people infer that there must be a signaling molecule induced by cell damage that plays an important regulatory role in tissue repair and organ regeneration. However, since scientists first discovered the regeneration phenomenon in 1740, the chemical nature of this signaling molecule has been unknown. In addition, the regeneration capacity of plants varies widely and varies between genotypes, which greatly limits the potential of breakthrough technologies such as transgenics and gene editing in biological breeding. Therefore, among the 125 major scientific questions unknown to mankind raised by Science magazine on the occasion of its 125th anniversary, "What regulates organ regeneration" was listed as one of the 25 most important scientific questions.

相比而言，人们对损伤引发植物再生的原初信号及其转导机制知之甚少。众所周知，细胞损伤是触发生命体（无论植物还是动物）启动再生程序的原初物理诱因。据此人们推断一定存在一种由细胞损伤诱发的信号分子在组织修复和器官再生过程中发挥重要调控作用。然而自从1740年科学家首次发现再生现象以来，人们对这种信号分子的化学本质却无从知晓。此外，植物的再生能力千差万别并且因基因型不同而异，这极大地制约着转基因和基因编辑等突破性技术在生物育种中的巨大应用潜力。因此，在《Science》杂志创刊125周年之际提出的125个人类未知的重大科学问题中，“是什么调控器官再生”被列为最重要的25个科学问题之一。

On May 22, 2024, Li Chuanyu's research group from Shandong Agricultural University/Institute of Genetics and Developmental Biology, Chinese Academy of Sciences published a research paper titled " Peptide REF1 is a local wound signal promoting plant regeneration " in the internationally renowned academic journal Cell . They identified for the first time the original wound signal molecule that induces plant regeneration - regeneration factor REF1 (REGENERATION FACTOR 1) , and systematically revealed the signal transduction network of REF1 regulating tissue repair and organ regeneration, and at the same time proved the great application value of REF1 in the fields of plant transgenics and gene editing.

2024年5月22日，中国山东农业大学/中国科学院遗传与发育生物学研究所李传友研究组在国际著名学术期刊Cell上发表题为《多肽REF1是一种促进植物再生的局部伤口信号》的研究论文，首次鉴定到诱发植物再生的原初受伤信号分子——再生因子REF1（REGENERATION FACTOR 1），并系统揭示了REF1调控组织修复和器官再生的信号转导网络，同时证明了REF1在植物转基因、基因编辑领域的巨大应用价值。

Li Chuanyou's team has long used tomatoes as a model to use genetic methods to analyze the plant systemic defense signaling pathway regulated by systemin and jasmonic acid. In the early stage, a series of spr (suppressor of prosystemin-mediated response) mutants with changes in the systemin signaling pathway were obtained through large-scale genetic screening. In order to analyze the plant regeneration process by genetic means, the team creatively proposed the following scientific concept: the plant's injury response actually includes two inseparable and interactive physiological processes, defense and regeneration. Based on this concept, it is inferred that tomato mutants related to regeneration should also show some degree of defects in defense response. Therefore, the study first started with the analysis of defense-deficient mutants accumulated in the laboratory, and identified a tomato mutant spr9 that was defective in both defense and regeneration. More importantly, spr9 had defects in both local and systemic defense responses, and lost the ability to form callus and organ regeneration, suggesting that SPR9 plays an important role in both injury-induced defense and regeneration responses.

李传友团队长期以番茄为模式用遗传学手段解析由系统素和茉莉酸共同调控的植物系统性防御信号通路。前期通过大规模的遗传筛选获得了一系列系统素信号通路发生变化的spr（原系统蛋白介导反应的抑制因子）突变体。为了用遗传学手段解析植物再生过程，团队创造性地提出了下述科学理念：植物的受伤反应实际上包括防御和再生两个密不可分而又相互作用的生理过程。基于该理念，推断再生相关的番茄突变体也应该在防御反应方面表现某种程度的缺陷。因此，研究首先从分析实验室积累的防御缺陷突变体入手，鉴定到防御和再生两个方面同时发生缺陷的番茄突变体spr9。尤为重要的是，spr9的局部防御反应和系统防御反应都发生缺陷，同时丧失了愈伤组织形成能力和器官再生能力，暗示SPR9在损伤诱发的防御反应和再生反应中均发挥重要作用。

Gene cloning results showed that SPR9 encodes the precursor protein of the small peptide SlPep (23 amino acids). Knockout of SPR9 caused tomatoes to lose their wound-induced callus formation and organ regeneration abilities, while overexpression of SPR9 significantly improved the regeneration ability of tomatoes. In addition, exogenous application of the small peptide encoded by SPR9 can also significantly improve the regeneration ability of tomatoes. Therefore, the small peptide was renamed regeneration factor REF1 .

基因克隆结果表明SPR9编码小肽SlPep（23个氨基酸）的前体蛋白。敲除SPR9使番茄丧失了受伤诱导的愈伤组织形成能力和器官再生能力，而过表达SPR9可显著提高番茄的再生能力。此外，外源施加SPR9编码的小肽也可以显著提高番茄的再生能力。因此将该小肽重新命名为再生因子REF1。

Studies have confirmed that the leucine-rich repeat receptor kinase PORK1 (PEPR1/2 ORTHOLOG RECEPTOR-LIKE KINASE 1) is the receptor of REF1. When cells are damaged in plants, REF1, as the original injury signal molecule, is recognized by the receptor PORK1 and activates the expression of the downstream key regulatory factor SlWIND1 for cell reprogramming, thereby initiating the process of tissue repair and organ regeneration. At the same time, SlWIND1 also binds to the promoter region of the REF1 precursor gene to activate its expression, thereby producing more REF1 small peptides and amplifying the REF1 signal. Therefore, REF1 regulates the regeneration process in a "plant cytokine" manner.

研究证实富含亮氨酸重复序列的受体激酶PORK1（PEPR1/2同源受体样激酶1）是REF1的受体。当植物发生细胞损伤时，REF1作为原初受伤信号分子被受体PORK1识别，并激活下游细胞重编程关键调控因子SlWIND1的表达，进而启动组织修复和器官再生进程。与此同时，SlWIND1还结合到REF1前体基因的启动子区激活其表达，从而产生更多的REF1小肽，放大REF1信号。因此，REF1以“植物细胞因子”的作用方式调控再生过程。

REF1 regulates the regeneration process by acting as a plant cytokine

REF1以植物细胞因子的作用方式调控再生过程

It is particularly important that the role of the regeneration factor REF1 is conserved in the plant kingdom. The corresponding REF1 peptide and its receptor can be found in almost all dicotyledonous and monocotyledonous plants. External application of REF1 can not only significantly improve the regeneration ability and genetic transformation efficiency of tomatoes (including some wild tomatoes that are difficult to transform), but also greatly improve the regeneration ability and genetic transformation efficiency of crops that are recognized to be difficult to transform, such as soybeans, wheat and corn. The relevant method has been applied for an international PCT patent (No. PCT/EP2023/064285).

尤为重要的是，再生因子REF1的作用在植物界是保守的。几乎在所有双子叶植物和单子叶植物中都能找到对应的REF1小肽及其受体。外施REF1不仅可以显著提高番茄（包括一些难以转化的野生番茄）的再生能力和遗传转化效率，还可以大幅度提高大豆、小麦和玉米等公认难以转化作物的再生能力和遗传转化效率。相关方法已申请国际PCT专利（No. PCT/EP2023/064285）。

REF1 can significantly improve the regeneration ability and genetic transformation efficiency of crops. (A) Tomato; (B) Soybean; (C) Wheat; (D) Corn

REF1可大幅度提高作物的再生能力和遗传转化效率。（A）番茄；（B）大豆；（C）小麦；（D）玉米

To sum up, this research is an important development in the mechanism of plant injury response. It not only found the original injury signal molecule REF1 that induces plant regeneration, solved a problem that has plagued the scientific community for centuries, but also provided a solution for crop genetic transformation in breeding practice. Bottleneck problems such as low efficiency and serious dependence on species and genotypes provide a convenient and universal solution.

综上所述，该研究是对植物受伤反应机理的重要发展，不仅找到了诱发植物再生的原初受伤信号分子REF1，破解了困扰科学界几个世纪的难题，而且为育种实践中解决作物遗传转化效率低、物种和基因型依赖严重等瓶颈问题提供了便捷普适的方案。

Doctoral student Yang Wentao , Associate Professor Zhai Huawei , Associate Researcher Wu Fangming and Professor Deng Lei are the co-first authors of the paper. Professor Li Chuanyou and Professor Deng Lei are the co-corresponding authors. Professor Zhang xiansheng , Professor Zhang Dajian , Professor Zhao xiangyu , Academician Li Jiayang and Researcher Gao Caixia participated in this research work. The research was funded by the National Natural Science Foundation of China, the National Key Research and Development Program and Taishan Tomato Innovation Research Institute.

博士研究生杨文韬、翟华伟副教授、吴芳明副研究员和邓磊教授为该论文的共同第一作者。李传友教授和邓磊教授为共同通讯作者。张宪省教授、张大健教授、赵翔宇教授、李家洋院士和高彩霞研究员参与了该研究工作。该研究得到了中国自然科学基金、中国重点研发计划和泰山番茄创新研究院的资助。

Since the first discovery of regeneration in 1740, scientists have not been clear about the original signal molecules that trigger plant regeneration after injury. On the other hand, since 1958, when scientists discovered that cultured carrot cells can regenerate into complete plants through the embryogenesis process, people have been paying attention to the factors that initially induce plant cell regeneration. Therefore, among the 125 major scientific problems unknown to mankind proposed by Science, "What regulates organ regeneration" and "How does a single somatic cell grow into a complete plant" are both listed as one of the 25 most important scientific problems. The discovery of plant regeneration factor REF1 depends on Chuanyou and others' creative proposal that the plant's injury response actually includes two inseparable and interactive physiological processes: defense and regeneration. This study is a major breakthrough in the long-standing unresolved issue in the field of plant life sciences, which is how plants recognize injury stimuli and initiate tissue repair and organ regeneration processes. Since the role of REF1 is conserved in the plant kingdom, exogenous application of REF1 can greatly improve the regeneration ability and genetic transformation efficiency of difficult-to-transform crops such as wheat, corn, and soybeans. This means that in addition to its great significance in basic research, this work also has important practical application prospects and should be a landmark scientific research achievement in the field of life sciences.

从1740年首次发现再生现象以来，科学家对损伤引发植物再生的原初信号分子一直并不清楚。而另一方面，自从1958年，科学家发现培养的胡萝卜细胞可以通过胚胎发生过程再生成完整植株以来，人们一直在关注最初诱导植物细胞再生的因素。因此，在《Science》提出的125个人类未知的重大科学问题中，“是什么调控器官再生”和“单个体细胞如何长成完整的植物”均被列为最重要的25个科学问题之一。植物再生因子REF1的发现取决于传友等人创造性地提出了植物的受伤反应实际上包括防御和再生两个密不可分而又相互作用的生理学过程。该研究对于植物如何识别损伤刺激并启动组织修复和器官再生过程这一植物生命科学领域长期悬而未决的问题，是一重大的进展。由于REF1的作用在植物界是保守的，外施REF1可以大幅度提高小麦、玉米、大豆等难转化作物的再生能力及遗传转化效率。这使得这项工作除了在基础研究中的重大意义外，还有着重要的实践应用前景，应是生命科学领域一个标志性的科研成果。

The development and application of biological breeding technology represented by gene editing is profoundly changing the global agricultural production and trade pattern, and the world's seed industry has entered the "4.0 era" of intelligent breeding. Making good use of the sharp sword of gene editing is of great significance to China in winning the battle to turn around the seed industry and carrying out technical research on the "stuck neck" of seed sources. The efficiency of transgenesis and gene editing depends on the regeneration capacity of the target plant. Therefore, studying the determining mechanism of plant regeneration ability is a core scientific issue in developing efficient gene transformation technology, and plays a decisive role in improving the efficiency of modern biological breeding. At present, most countries in the world use the strategy of co-expression of developmental regulatory genes to improve plant regeneration ability. However, this method has limited improvement in crop genetic transformation efficiency and often leads to developmental defective phenotypes of transgenic plants. The discovery of the regeneration factor REF1 not only successfully overcomes the above limitations, but is also convenient and efficient, providing a universal solution to bottleneck problems such as low crop genetic transformation efficiency and serious dependence on species and genotypes in biological breeding practices. It is believed that the research results will play an important role in China's major strategic layout of accelerating the industrialization of biological breeding.

以基因编辑为代表的生物育种技术的发展与应用正深刻改变着全球农产品生产和贸易格局，世界种业进入到智能育种“4.0时代”。用好基因编辑这把利剑对我国打赢种业翻身仗、开展种源 “卡脖子” 技术攻关具有重大意义。转基因和基因编辑的效率取决于目标植物的再生能力。因而研究植物再生能力的决定机制是研发高效基因转化技术的核心科学问题，对于提高现代生物育种的效率具有决定性作用。目前国际上大多采用共表达发育调控基因的策略提高植物再生能力，但这种方法对作物遗传转化效率的提升有限，而且常会导致转基因植物的发育缺陷表型。再生因子REF1的发现不仅成功克服了上述局限，而且便捷高效，为生物育种实践中解决作物遗传转化效率低、物种和基因型依赖严重等瓶颈问题提供了普适方案。相信该研究成果一定会在我国加快推进生物育种产业化步伐的重大战略布局中发挥重要作用。