The scarless heart and the MRL mouse

The ability to regenerate tissues and limbs in its most robust form is seen in many non-mammalian species. The serendipitous discovery that the MRL mouse has a profound capacity for regeneration in some ways rivalling the classic newt and axolotl species raises the possibility that humans, too, may have an innate regenerative ability. The adult MRL mouse regrows cartilage, skin, hair follicles and myocardium with near perfect fidelity and without scarring. This is seen in the ability to close through-and-through ear holes, which are generally used for lifelong identification of mice, and the anatomic and functional recovery of myocardium after a severe cryo-injury. We present histological, biochemical and genetic data indicating that the enhanced breakdown of scar-like tissue may be an underlying factor in the MRL regenerative response. Studies as to the source of the cells in the regenerating MRL tissue are discussed. Such studies appear to support multiple mechanisms for cell replacement.     

Human adult pluripotency: Facts and questions

Cellular reprogramming and induced pluripotent stem cell(IPSC) technology demonstrated the plasticity of adult cell fate, opening a new era of cellular modelling and introducing a versatile therapeutic tool for regenerative medicine.While IPSCs are already involved in clinical trials for various regenerative purposes, critical questions concerning their medium-and long-term genetic and epigenetic stability still need to be answered. Pluripotent stem cells have been described in the last decades in various mammalian and human tissues(such as bone marrow, blood and adipose tissue). We briefly describe the characteristics of human-derived adult stem cells displaying in vitro and/or in vivo pluripotency while highlighting that the common denominators of their isolation or occurrence within tissue are represented by extreme cellular stress. Spontaneous cellular reprogramming as a survival mechanism favoured by senescence and cellular scarcity could represent an adaptative mechanism. Reprogrammed cells could initiate tissue regeneration or tumour formation dependent on the microenvironment characteristics. Systems biology approaches and lineage tracing within living tissues can be used to clarify the origin of adult pluripotent stem cells and their significance for regeneration and disease.     

Compartments and distal outgrowth in theDrosophila imaginal wing disc

Summary Peripheral tissue of the imaginal wing disc gives rise to the proximal mesothoracic structures of the adult. Pieces of peripheral tissue, which have no regenerative capacity when cultured as intact fragments, are capable of distal outgrowth (regeneration) after dissociation and reaggregation. This ability depends on the region of the disc periphery from which the fragment is taken. Extensive distal outgrowth occurs in reaggreages of a fragment containing equal proportions of tissue from anterior and posterior developmental compartments. The extent of outgrowth decreases as the proportion of posterior tissue is reduced, so that a fragment containing only anterior tissue shows no regeneration after dissociation. Limited distal outgrowth occurs in reaggregates of a wholly posterior fragment, but the regenerative capacity is increased greatly when a small amount of anterior tissue is included. It is concluded that distal outgrowth in the wing disc requires an interaction between cells of the anterior and posterior compartments.     

Natural regeneration potential of abandoned agricultural land in the southern Gadarif Region,Sudan: implications for conservation

The present study seeks to provide a contribution to the understanding of vegetation regrowth on abandoned agricultural land by investigating the impacts of the previous cultivation period and the duration of the fallow on the subsequent natural regeneration in terms of vegetation composition, structure and diversity. The results of the study show that both factors have significant effects on the subsequent regeneration of plant species and thus the vegetation development in the southern Gadarif Region, Sudan. The oldest abandoned farmlands were recolonized by tree/shrub species, whereas recently abandoned ones are covered with herbaceous vegetation. There is a general tendency regarding the number of species to decrease with an increase in the period of cultivation. The plant species diversity pattern shows domination of herbaceous species with some scattered woody species. Vegetation changes due to land abandonment may have implications for the conservation of plant species diversity and composition of fauna harboured in the region. Although natural regeneration could be recommended as means of restoring natural vegetation that previously dominated that region, the current regeneration capacity might not be sufficient to reach the climax vegetation except for some pockets, which received more regenerative resources.     

斑马鱼在再生医学研究中的应用及进展

组织器官的再生现象一直以来吸引着众多生物学家们的关注。再生能力在不同物种间差异很大, 与人及高等脊椎动物相比, 低等脊椎动物(如：斑马鱼)有着较高的再生能力。斑马鱼的鳍、心脏、视网膜、视神经、脊髓、肝脏及感觉毛细胞等都具有很强的再生能力。因此, 从斑马鱼再生过程的研究中将获得大量有用的信息, 促进对人类再生能力缺陷的认识, 进而推动再生医学的发展。文章就斑马鱼在心脏、神经系统、肝脏、鳍再生医学研究中的进展及应用做一综述。     

Regenerative therapy for neuronal diseases with transplantation of somatic stem cells

Pluripotent stem cells, which are capable of differentiating in various species of cells, are hoped to be donor cells in transplantation in regenerative medicine. Embryonic stem (ES) cells and induced pluripotent stem cells have the potential to differentiate in approximately all species of cells. However, the proliferating ability of these cells is high and the cancer formation ability is also recognized. In addition, ethical problems exist in using ES cells. Somatic stem cells with the ability to differentiate in various species of cells have been used as donor cells for neuronal diseases, such as amyotrophic lateral sclerosis, spinal cord injury, Alzheimer disease, cerebral infarction and congenital neuronal diseases. Human mesenchymal stem cells derived from bone marrow, adipose tissue, dermal tissue, umbilical cord blood and placenta are usually used for intractable neuronal diseases as somatic stem cells, while neural progenitor/stem cells and retinal progenitor/stem cells are used for a few congenital neuronal diseases and retinal degenerative disease, respectively. However, non-treated somatic stem cells seldom differentiate to neural cells in recipient neural tissue. Therefore, the contribution to neuronal regeneration using non-treated somatic stem cells has been poor and various differential trials, such as the addition of neurotrophic factors, gene transfer, peptide transfer for neuronal differentiation of somatic stem cells, have been performed. Here, the recent progress of regenerative therapies using various somatic stem cells is described.     

Survey of the differences between regenerative and non-regenerative animals

To investigate the boundaries between regenerative and non-regenerative animals, we first survey regenerative ability across animal phyla from sponges to chordates (including mammals). There are both regenerative and non-regenerative animals in each phylum. The cells participating in regeneration also vary among different species. Thus, it is hard to find clear rules concerning regeneration ability across the animal kingdom, suggesting that it is not useful to compare the difference of regenerative ability across phyla to seek the boundary between regenerative and non-regenerative animals. Instead, if we carefully compare the differences of regenerative ability between closely related species within each phylum and accumulate these differences at the cellular molecular levels, we may be able to clarify the boundary between regenerative and non-regenerative animals. Here we introduce our comparative analysis of cellular events after amputation of lower jaws between frogs and newts. Then we propose that such comparative analyses using closely related species within the same phylum should be accumulated to understand the boundary between regenerative and non-regenerative animals in order to apply this understanding for realizing regenerative medicine in the future.     

Variation in Salamander Tail Regeneration Is Associated with Genetic Factors That Determine Tail Morphology

Very little is known about the factors that cause variation in regenerative potential within and between species. Here, we used a genetic approach to identify heritable genetic factors that explain variation in tail regenerative outgrowth. A hybrid ambystomatid salamander (Ambystoma mexicanum x A. andersoni) was crossed to an A. mexicanum and 217 offspring were induced to undergo metamorphosis and attain terrestrial adult morphology using thyroid hormone. Following metamorphosis, each salamander’s tail tip was amputated and allowed to regenerate, and then amputated a second time and allowed to regenerate. Also, DNA was isolated from all individuals and genotypes were determined for 187 molecular markers distributed throughout the genome. The area of tissue that regenerated after the first and second amputations was highly positively correlated across males and females. Males presented wider tails and regenerated more tail tissue during both episodes of regeneration. Approximately 66–68% of the variation in regenerative outgrowth was explained by tail width, while tail length and genetic sex did not explain a significant amount of variation. A small effect QTL was identified as having a sex-independent effect on tail regeneration, but this QTL was only identified for the first episode of regeneration. Several molecular markers significantly affected regenerative outgrowth during both episodes of regeneration, but the effect sizes were small (<4%) and correlated with tail width. The results show that ambysex and minor effect QTL explain variation in adult tail morphology and importantly, tail width. In turn, tail width at the amputation plane largely determines the rate of regenerative outgrowth. Because amputations in this study were made at approximately the same position of the tail, our results resolve an outstanding question in regenerative biology: regenerative outgrowth positively co-varies as a function of tail width at the amputation site.     

Human regeneration: An achievable goal or a dream?

The main objective of regenerative medicine is to replenish cells or tissues or even to restore different body parts that are lost or damaged due to disease, injury and aging. Several avenues have been explored over many decades to address the fascinating problem of regeneration at the cell, tissue and organ levels. Here we discuss some of the primary approaches adopted by researchers in the context of enhancing the regenerating ability of mammals. Natural regeneration can occur in different animal species, and the underlying mechanism is highly relevant to regenerative medicine-based intervention. Significant progress has been achieved in understanding the endogenous regeneration in urodeles and fishes with the hope that they could help to reach our goal of designing future strategies for human regeneration.     

Early gene expression during natural spinal cord regeneration in the salamander Ambystoma mexicanum

In contrast to mammals, salamanders have a remarkable ability to regenerate their spinal cord and recover full movement and function after tail amputation. To identify genes that may be associated with this greater regenerative ability, we designed an oligonucleotide microarray and profiled early gene expression during natural spinal cord regeneration in Ambystoma mexicanum. We sampled tissue at five early time points after tail amputation and identified genes that registered significant changes in mRNA abundance during the first 7 days of regeneration. A list of 1036 statistically significant genes was identified. Additional statistical and fold change criteria were applied to identify a smaller list of 360 genes that were used to describe predominant expression patterns and gene functions. Our results show that a diverse injury response is activated in concert with extracellular matrix remodeling mechanisms during the early acute phase of natural spinal cord regeneration. We also report gene expression similarities and differences between our study and studies that have profiled gene expression after spinal cord injury in rat. Our study illustrates the utility of a salamander model for identifying genes and gene functions that may enhance regenerative ability in mammals.     

Cellular and molecular mechanisms of regeneration in Xenopus

We have employed transgenic methods combined with embryonic grafting to analyse the mechanisms of regeneration in Xenopus tadpoles. The Xenopus tadpole tail contains a spinal cord, notochord and segmented muscles, and all tissues are replaced when the tail regenerates after amputation. We show that there is a refractory period of very low regenerative ability in the early tadpole stage. Tracing of cell lineage with the use of single tissue transgenic grafts labelled with green fluorescent protein (GFP) shows that there is no de-differentiation and no metaplasia during regeneration. The spinal cord, notochord and muscle all regenerate from the corresponding tissue in the stump; in the case of the muscle the satellite cells provide the material for regeneration. By using constitutive or dominant negative gene products, induced under the control of a heat shock promoter, we show that the bone morphogenetic protein (BMP) and Notch signalling pathways are both essential for regeneration. BMP is upstream of Notch and has an independent effect on regeneration of muscle. The Xenopus limb bud will regenerate completely at the early stages but regenerative ability falls during digit differentiation. We have developed a procedure for making tadpoles in which one hindlimb is transgenic and the remainder wild-type. This has been used to introduce various gene products expected to prolong the period of regenerative capacity, but none has so far been successful.     

Analysis of expression profiles of selected genes associated with the regenerative property and the receptivity to gene transfer during somatic embryogenesis in Triticum aestivum L.

The physiological, biochemical and molecular mechanisms regulating the initiation of a regenerative pathway remain partially unknown. Efforts to identify the biological features that confer transformation ability, or the tendency of some cells to induce transgene silencing, would help to improve plant genetic engineering. The objective of our study was to monitor the evolution of plant cell competencies in relation to both in vitro tissue culture regeneration and the genetic transformation properties. We used a simple wheat regeneration procedure as an experimental model for studying the regenerative capacity of plant cells and their receptivity to direct gene transfer over the successive steps of the regenerative pathway. Target gene profiling studies and biochemical assays were conducted to follow some of the mechanisms triggered during the somatic-to-embryogenic transition (i.e. dedifferentiation, cell division activation, redifferentiation) and affecting the accessibility of plant cells to receive and stably express the exogenous DNA introduced by bombardment. Our results seem to indicate that the control of cell-cycle (S-phase) and host defense strategies can be crucial determinants of genetic transformation efficiency. The results from studies conducted at macro-, micro- and molecular scales are then integrated into a holistic approach that addresses the question of tissue culture and transgenesis competencies more broadly. Through this multilevel analysis we try to establish functional links between both regenerative capacity and transformation receptiveness, and thereby to provide a more global and integrated vision of both processes, at the core of defense/adaptive mechanisms and survival, between undifferentiated cell proliferation and organization.     

Vegetation dynamics of Mediterranean shrublands in former cultural landscape at Grazalema Mountains,South Spain

Plant community dynamics in Mediterranean basin ecosystems are mainly driven by an alternation of episodes of human intervention and land abandonment. As a result, a mosaic of plant communities has evolved following different stages of degradation and regeneration. Some authors has relate secondary succession to abandoned culture lands and regeneration to natural systems with abandonment of livestock or forestry exploitation. In this paper, the dynamics of shrublands in mid-mountain areas in the South of Spain after disturbance and land abandonment has been studied. The plant cover and 13 environmental variables of 137 selected sites on the Grazalema mountains was analysed to determine the vegetation pattern in relation to environmental factors and the succession types, either regenerative or secondary succession. The results show that today the Grazalema mountains have a heterogeneous vegetation pattern. Besides physical factors such as altitude or soil , human disturbance has modulated current vegetation patterns and dynamics. Two main types of vegetation dynamics can be distinguished in the study area. In areas affected by cutting, regeneration results in rich and dense shrub land, with resprouters as dominant species. In areas affected by recurrent wildfires or agriculture, secondary succession became dominant, resulting in less diverse shrubland, due to the dominance of seeders and decrease in resprouter species richness and cover.     

海鞘再生的细胞学过程及其调控机制研究进展与展望

再生现象在后生动物中普遍存在,但不同物种的再生能力存在显著差别.无脊椎动物如水螅和涡虫等再生能力较强,具有部分组织或细胞即可再生出一个完整个体的能力,被称为整体再生;而脊椎动物的再生能力相对较弱,局限在某些特定器官或身体结构,被称为部分再生,如蝾螈的附肢.海鞘作为进化上介于无脊椎动物与脊椎动物之间的尾索动物,既包括具备...     

Cardiac regeneration as an environmental adaptation

Heart failure is a devastating disease that affects more than 26 million individuals worldwide and has a 5-year survival rate of less than 50%, with its development in part reflecting the inability of the adult mammalian heart to regenerate damaged myocardium. In contrast, certain vertebrate species including fish and amphibians, as well as neonatal mammals, are capable of complete cardiac regeneration after various types of myocardial injury such as resection of the ventricular apex or myocardial infarction, with this regeneration being mediated by the proliferation of cardiomyocytes, dissolution of temporary fibrosis, and revascularization of damaged tissue. In an effort to identify regulators of cardiac regeneration and to develop novel therapeutic strategies for induction of myocardial regeneration in the adult human heart, recent studies have adopted an approach based on comparative biology. These studies have pointed to cellular or tissue responses to environmental cues—including activation of the immune system, the reaction to mechanical stress, and the adoption of oxidative metabolism—as key determinants of whether the heart undergoes regeneration or nonregenerative scar formation after injury. We here summarize recent insight into the molecular mechanisms as well as environmental and systemic factors underlying cardiac regeneration based on the findings of inter- or intraspecific comparisons between regenerative and nonregenerative responses to heart injury. We also discuss how recent progress in understanding the molecular, systemic, and environmental basis of cardiac regeneration in a variety of organisms may relate to multiple scientific fields including ecology, evolutionary as well as developmental biology.     

Evolutionary modification of regenerative capability in vertebrates: a comparative study on teleost pectoral fin regeneration.

The regenerative ability of the pectoral fins of 14 species from 6 euteleostean families was tested. Blastema formation and distal outgrowth was observed in all species, indicating the initiation of regeneration in all species tested. Interspecific variation exists with respect to the frequency of malformations and the patterns produced by heteromorphic regeneration. Taking into account published reports on pectoral fin regeneration, the systematic distribution of homo- and heteromorphic regeneration leads to the following conclusions: 1) regenerative ability of pectoral fins is a property inherited from the common ancestor of euteleosteans. Whether it is also the ancestral condition for the whole teleostean group cannot be determined, because reports on more primitive teleosteans like the herring and the osteoglossimorphs are missing. 2) A propensity to produce high frequencies of heteromorphic regenerates originated independently at least three times in Cypriniformes, Scorpaeniformes, and Perciformes. 3) Impaired regeneration is most commonly found in bottom fishes, although not all ground fish groups show heteromorphic regeneration. This suggests that impaired regeneration is not directly related to bottom dwelling, but most probably originated as a side effect of other adaptive changes. Hence, neither the presence nor the loss of faithful regeneration can be associated with particular adaptive scenarios in this group, since regeneration seems to be ancestral to all major euteleost groups and its loss has no clear adaptive significance. Whether there are adaptive reasons to maintain regenerative capability or whether there are cases of reestablishment of regeneration after it was lost cannot be decided on the basis of recent evidence. More observations on phylogenetically closely related species with variable regenerative capability are necessary to assess adaptive explanations of regeneration.     

Regenerative medicine for diseases of the head and neck: principles of in vivo regeneration

The application of endogenous regeneration in regenerative medicine is based on the concept of inducing regeneration of damaged or lost tissues from residual tissues in situ. Therefore, endogenous regeneration is also termed in vivo regeneration as opposed to mechanisms of ex vivo regeneration which are applied, for example, in the field of tissue engineering. The basic science foundation for mechanisms of endogenous regeneration is provided by the field of regenerative biology. The ambitious vision for the application of endogenous regeneration in regenerative medicine is stimulated by investigations in the model organisms of regenerative biology, most notably hydra, planarians and urodeles. These model organisms demonstrate remarkable regenerative capabilities, which appear to be conserved over large phylogenetical stretches with convincing evidence for a homologue origin of an endogenous regenerative capability. Although the elucidation of the molecular and cellular mechanisms of these endogenous regenerative phenomena is still in its beginning, there are indications that these processes have potential to become useful for human benefit. Such indications also exist for particular applications in diseases of the head and neck region. As such epimorphic regeneration without blastema formation may be relevant to regeneration of sensorineural epithelia of the inner ear or the olphactory epithelium. Complex tissue lesions of the head and neck as they occur after trauma or tumor resections may be approached on the basis of relevant mechanisms in epimorphic regeneration with blastema formation.     

Regenerative interactions between Drosophila imaginal discs of different types.

We have tested the ability of fragments of one type of imaginal disc to stimulate regeneration of another type. It has been shown by others that, when extreme proximal and distal fragments of the wing disc are combined, intercalary regeneration of the missing tissue ensues. Each fragment, if cultured alone, will merely duplicate its structures. We now find that distal fragments of other thoracic discs, haltere and leg, while retaining their autonomy for differentiation, also interact with proximal wing tissue to promote regeneration of more distal wing structures. The proximal wing tissue used in these experiments was the wingless abnormal wing disc which, in the absence of interaction, yields only proximal wing structures. These results suggest that spatial organization is controlled by similar systems in the various thoracic discs. In contrast, head and genital disc material provided no regenerative stimulus to the mutant wing disc tissue.