Cells and tissue within injured organs undergo a complicated healing process that still remains poorly understood. Interestingly, smaller organisms respond to injury with tissue regeneration and restoration of function, while humans and other large organisms respond to injury by forming dysfunctional, fibrotic scar tissue. Over the past few decades, allometric scaling principles have been well established to show that larger organisms experience exponentially higher tissue forces during movement and locomotion and throughout the organism's lifespan. How (...) these evolutionary adaptations may affect tissue injury has not been thoroughly investigated in humans. We discuss how these adapations may affect healing and demonstrate that blocking the most evolutionary conserved biologic force sensor enables large organisms to heal after injury with true tissue regeneration. Future strategies to disrupt tissue force sensors may unlock the key to regenerating after injury in a wide range of organ systems. (shrink)

Most tissues contain cells capable of the self‐renewal and differentiation necessary to maintain tissue and organ integrity. These somatic stem cells are generally thought to have limited developmental potential. The mechanisms that restrict cell fate decisions in somatic stem cells are only now being understood. This understanding will be important in the clinical exploitation of adult stem cells in tissue repair and replacement. Experiments performed over fifty years ago in Drosophila showed that developmental restriction could be relaxed in (...) the proliferating larval cells that are destined to form the adult fly integument. This phenomenon, called transdetermination, can serve as a model for mechanisms of stem‐cell commitment. A recent publication1 sheds new light on the mechanism of transdetermination by demonstrating that loss of homeotic gene silencing leads to increased frequency of transdetermination. In addition, the authors link a specific signaling pathway induced by tissue regeneration to the relaxation of homeotic gene silencing. The data identify key mechanisms that control developmental homeostasis and cell fate restriction that could be manipulated to make somatic stem‐cell engineering possible. BioEssays 28: 574–577, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Regenerative medicine promises to greatly impact on human health by improving repair outcomes in a range of tissues and injury contexts. Successful therapies will rely on identifying both intrinsic and extrinsic biological circuits that control wound healing, proliferation, cell survival, and developmental cell fate. Animals such as the zebrafish and the salamander display powerful examples of near‐perfect regeneration and scar‐free healing in a range of injury contexts not attained in mammals. By studying regeneration in a range of highly (...) regenerative species that maintain regenerative potential throughout life, many instructive and permissive factors have been identified that could assist in the development of regenerative therapies. This review highlights some of the recent observations in immune regulation, epigenetic regulation, stem cell mobilization, and regenerative signatures that have improved our understanding of the regenerative process. Potential opportunities in harnessing this knowledge for future translation into the clinic are discussed. (shrink)

We propose that interaction rules derived from polyamine exchange in connected cells may explain the spatio‐temporal organization of gap junctions observed during tissue regeneration and tumorigenesis. We also hypothesize that polyamine exchange can be considered as signal that allows cells to sense the proliferation status of their neighbors. Polyamines (putrescine, spermidine, and spermine) are indeed small aliphatic polycations that serve as fuels to sustain elevated proliferation rates of the order observed in cancer cells. Based on recent reports, we (...) consider here that polyamines can be exchanged through gap junction channels between mammalian cells. Such intercellular exchange of polyamines has critical consequences on the local control of growth. In line with this hypothesis, the complex protein network that keeps polyamine levels finely tuned in mammalian cells can translate polyamine efflux or influx into integrated signals controlling transcription, translation, and cell communications. (shrink)

The processes of wound healing and bone regeneration and problems in tissue engineering have been an active area for mathematical modeling in the last decade. Here we review a selection of recent models which aim at deriving strategies for improved healing. In wound healing, the models have particularly focused on the inflammatory response in order to improve the healing of chronic wound. For bone regeneration, the mathematical models have been applied to design optimal and new treatment strategies (...) for normal and specific cases of impaired fracture healing. For the field of tissue engineering, we focus on mathematical models that analyze the interplay between cells and their biochemical cues within the scaffold to ensure optimal nutrient transport and maximal tissue production. Finally, we briefly comment on numerical issues arising from simulations of these mathematical models. (shrink)

Platelets have important hemostatic functions in repairing blood vessels upon tissue injury. Cytokines, growth factors, and metabolites stored in platelet α‐granules and dense granules are released upon platelet activation and clotting. Emerging evidence indicates that such platelet‐derived signaling factors are instrumental in guiding tissue regeneration. Here, we discuss the important roles of platelet‐secreted signaling factors in skeletal muscle regeneration. Chemokines secreted by platelets in the early phase after injury are needed to recruit neutrophils to injured muscles, (...) and impeding this early step of muscle regeneration exacerbates inflammation at later stages, compromises neo‐angiogenesis and the growth of newly formed myofibers, and reduces post‐injury muscle force production. Platelets also contribute to the recruitment of pro‐regenerative stromal cells from the adipose tissue, and the platelet releasate may also regulate the metabolism and proliferation of muscle satellite cells, which sustain myogenesis. Therefore, harnessing the signaling functions of platelets and the platelet secretome may provide new avenues for promoting skeletal muscle regeneration in health and disease. (shrink)

The convergence of morphogenesis into viable organisms under variable conditions suggests closed‐loop dynamics involving multiscale functional feedback. We develop the idea that morphogenesis is based on synergy between mechanical and bio‐signaling processes, spanning all levels of organization: molecular, cellular, tissue, up to the whole organism. This synergy provides feedback within and between all levels of organization, to close the loop between the dynamics of the morphogenesis process and its robust functional outcome. Hydra offer a powerful platform to explore this (...) direction, thanks to their simple body plan, extraordinary regeneration capabilities, and the accessibility and flexibility of their tissues. Our recent experiments show that structural inheritance of the actomyosin organization directs body‐axis formation during Hydra regeneration. Morphogenesis is then stabilized through dynamic cytoskeletal reorganization induced by the inherited structure. The observed cytoskeletal stability and reorganization capabilities suggest that mechanical feedback integrates with biochemical processes to establish viable patterns and ensure canalization. (shrink)

• Aggregates of previously isolated cells of Hydra are capable, under suitable solvant conditions, of regeneration forming complete animals. In a first stage, ecto- and endodermal cells sort out, producing the bilayered hollow structure characteristic of Hydra tissue; thereafter, heads are formed (even if the original cell preparation contained no head cells), eventually leading to the separation of normal animals with head, body column and foot. Hydra appears to be the highest type of organism that allows for (...) class='Hi'>regeneration of the entire structure from random cell aggregates. The system is particularly useful for studying cell interactions, tissue polarity, pattern formation, and cell differentiation. (shrink)

Ex-vivo tissue engineering is a quickly developing medical technology aiming to regenerate tissue through the introduction of an ex-vivo created tissue construct instead of restoring the damaged tissue to some level of functionality. Tissue engineering is considered by some as a new medical paradigm. We analyse this claim and identify tissue engineering’s fundamental characteristics, focusing on the aim of the intervention and on the complexity and continuity of the process. We inquire how these features (...) have an impact not only on the scientific research itself but also on the ethical evaluation of this research. We suggest that viewing tissue engineering as a new medical paradigm allows us to develop a wider perspective for successful investigation instead of focusing on isolated steps of the tissue engineering process in an anecdotal way, which may lead to an inadequate ethical evaluation. We argue that the concept of tissue engineering as a paradigm may benefit the way we address the ethical challenges presented by tissue engineering. (shrink)

Embryonic and adult field do not exhibit the same properties because they are formed by cell populations whose activities cannot be compared in all respects. Dominant cells are not distributed in the same manner; the same mechanisms are not involved for remodelling of the field, especially after an amputation.In adult organisms, cell equilibrium is disturbed a first time by elimination of differentiated tissues which provokes dedifferentiation and proliferation, and a second time by healing, which restores cell equilibrium of a distal (...) end. Undifferentiated cells begin to differentiate immediately after their production and they reform the missing levels, following a sequence either basipetal or basifugal according to the place of their production . The differentiating regenerate temporarily exhibits embryonic field properties in various experimental conditions which suppress the dominance of the stump or supplies additional undifferentiated material. (shrink)

The origin of insulin‐expressing β‐cells in the adult mammalian pancreas is controversial. During normal tissue turnover and following injury, β‐cells may be replaced by duplication of existing β‐cells.1 However, an alternative source of β‐cells has recently been proposed based on neogenesis from a Ngn3‐positive population present in regenerating pancreatic ducts.2 The appearance of β‐cells from Ngn3‐positive progenitors is reminiscent of normal pancreas development, and Ngn3‐expressing cells isolated from regenerating pancreas can generate the full repertoire of endocrine phenotypes. The isolation (...) and characterisation of the equivalent human progenitors may represent a significant step forward in the hunt for a cure for diabetes. BioEssays 30:617–620, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

We recently examined gene expression during Xenopus tadpole tail appendage regeneration and found that carbohydrate regulatory genes were dramatically altered during the regeneration process. In this essay, we speculate that these changes in gene expression play an essential role during regeneration by stimulating the anabolic pathways required for the reconstruction of a new appendage. We hypothesize that during regeneration, cells use leptin, slc2a3, proinsulin, g6pd, hif1α expression, receptor tyrosine kinase (RTK) signaling, and the production of reactive (...) oxygen species (ROS) to promote glucose entry into glycolysis and the pentose phosphate pathway (PPP), thus stimulating macromolecular biosynthesis. We suggest that this metabolic shift is integral to the appendage regeneration program and that the Xenopus model is a powerful experimental system to further explore this phenomenon.Also watch the Video Abstract. (shrink)

Mesenchymal stem cells (MSCs) are present in fat tissues throughout the body, yet little is known regarding their biological role within epidural fat. We hypothesize that debridement of epidural fat and/or subsequent loss of MSCs within this tissue, disrupts homeostasis in the vertebral environment resulting in increased inflammation, fibrosis, and decreased neovascularization leading to poorer functional outcomes post‐injury/operatively. Clinically, epidural fat is commonly considered a space‐filling tissue with limited functionality and therefore typically discarded during surgery. However, the presence (...) of MSCs within epidural fat suggests that itis more biologically active than historically believed and may contribute to the regulation of homeostasis and regeneration in the dural environment. While the current literature supports our hypothesis, it will require additional experimentation to determine if epidural fat is an endogenous driver of repair and regeneration and if so, this tissue should be minimally perturbed from its original location in the spinal canal. Also see the video abstract here https://youtu.be/MIol_IWK1os. (shrink)

This paper is devoted to computer modelling of the development and regeneration of multicellular biological structures. Some species are able to regenerate parts of their body after amputation damage, but the global rules governing cooperative cell behaviour during morphogenesis are not known. Here, we consider a simplified model organism, which consists of tissues formed around special cells that can be interpreted as stem cells. We assume that stem cells communicate with each other by a set of signals, and that (...) the values of these signals depend on the distance between cells. Thus the signal distribution characterizes location of stem cells. If the signal distribution is changed, then the difference between the initial and the current signal distribution affects the behaviour of stem cells—e.g. as a result of an amputation of a part of tissue the signal distribution changes which stimulates stem cells to migrate to new locations, appropriate for regeneration of the proper pattern. Moreover, as stem cells divide and form tissues around them, they control the form and the size of regenerating tissues. This two-level organization of the model organism, with global regulation of stem cells and local regulation of tissues, allows its reproducible development and regeneration. (shrink)

The acoel worm Symsagittifera roscoffensis, an early offshoot of the Bilateria and the only well‐studied marine acoel that lives in a photosymbiotic relationship, exhibits a centralized nervous system, brain regeneration, and a wide repertoire of complex behaviors such as circatidal rhythmicity, photo/geotaxis, and social interactions. While this animal can be collected by the thousands and is studied historically, significant progress is made over the last decade to develop it as an emerging marine model. The authors here present the feasibility (...) of culturing it in the laboratory and describe the progress made on different areas, including genomic and tissue architectures, highlighting the associated challenges. In light of these developments, and on the ability to access abundant synchronized embryos, the authors put forward S. roscoffensis as a marine system to revisit questions in the areas of photosymbiosis, regeneration, chronobiology, and the study of complex behaviors from a molecular and evolutionary perspective. (shrink)

This paper is devoted to computer modelling of the development and regeneration of multicellular biological structures. Some species are able to regenerate parts of their body after amputation damage, but the global rules governing cooperative cell behaviour during morphogenesis are not known. Here, we consider a simplified model organism, which consists of tissues formed around special cells that can be interpreted as stem cells. We assume that stem cells communicate with each other by a set of signals, and that (...) the values of these signals depend on the distance between cells. Thus the signal distribution characterizes location of stem cells. If the signal distribution is changed, then the difference between the initial and the current signal distribution affects the behaviour of stem cells—e.g. as a result of an amputation of a part of tissue the signal distribution changes which stimulates stem cells to migrate to new locations, appropriate for regeneration of the proper pattern. Moreover, as stem cells divide and form tissues around them, they control the form and the size of regenerating tissues. This two-level organization of the model organism, with global regulation of stem cells and local regulation of tissues, allows its reproducible development and regeneration. (shrink)

Ex-vivo tissue engineering is an emerging medical technology. Its aim is to regenerate tissues and organs and to restore them to full physiological activity. Some clinical trials with human tissue engineered products have been conducted and others will follow. These trials not only have to confirm the therapeutic value of the HTEP, they also have to provide insight in its regenerative activity, its safety and long-term effects. The development of these trials is aggravated by the complexity of the (...) tissue engineering process and product. This paper investigates how this complexity influences the ethical conduct of clinical trials with HTEPs. We focus on the value and validity of the trial, the risk-benefit ratio and the protection of the trial participant. We argue that trials with HTEPs need a robust methodology. The risk-benefit ratio of a new HTEP must be determined and compared with available efficacious therapies. This requires the identification and minimisation of risks associated with tissue engineering. Finally a process as complex as tissue engineering presents serious challenges for the informed consent process, and for the protection of the trial participant during and after the trial. (shrink)

In the minds of many, Hox gene null mutant phenotypes have confirmed the direct role that these genes play in specifying the pattern of vertebrate embryos. The genes are envisaged as defining discrete spatial domains and, subsequently, conferring specific segmental identities on cells undergoing differentiation along the antero‐posterior axis. However, several aspects of the observed mutant phenotypes are inconsistent with this view. These include: the appearance of other, unexpected transformations along the dorsal axis; the occurrence of mirror‐image duplications; and the (...) development of anomalies outside the established domains of normal Hox gene expression. In this paper, Hox gene disruptions are shown to elicit regeneration‐like responses in tissues confronted with discontinuities in axial identity. The polarities and orientations of transformed segments which emerge as a consequence of this response obey the rules of distal transformation and intercalary regeneration. In addition, the incidence of periodic anomalies suggests that the initial steps of Hox‐mediated patterning occurs in Hensen's node. As gastrulation proceeds, mesoderm cell cycle kinetics impose constraints upon subsequent cellular differentiation. This results in the delayed manifestation of transformations along the antero‐posterior axis. Finally, a paradigm is sketched in which temporal, rather than spatial axial determinants direct differentiation. Specific, testable predictions are made about the role of Hox genes in the establishment of segmental identity. (shrink)

Impaired liver function can be seen from increased levels (SGOT-SGPT) due to proinflammatory cytokines TNF-α, (iL-1) and (iL-6) which inhibit hormone production (PDGF) in the process of liver tissue regeneration. The formulation of Phyllanthus niruri L. and Phyllanthus urinaria L. combined with toman fish albumin is a combination that can work synergistically in suppressing the production of proinflammatory molecules, because the combination contains compounds that are antioxidants. A total of 24 male Rattus norvegicus were divided into four treatment (...) groups, namely: negative control (healthy), CCl4-induced positive control, dose 1 formulation and dose 2 formulation. Male rattus norvegicus induced CCl4 of 3 ml/kg intraperitoneally, to describe impaired liver function. Male rattus norvegicus was given formula (Phyllanthus niruri L. with Toman fish albumin) and (Phyllanthus urinaria L. and Toman fish albumin) orally at a dose of 1 (620 mg/200 g body weight: 62 mg/200 g body weight), and dose 2 (1240 mg/200 g body weight: 124 mg/200 g body weight) for 14 days. SGOT-SGPT levels were analyzed with a flowcytometer on the first day after acclimatization and day 14, and analysis of proinflammatory cytokines (TNF-α + iL-1 + iL-6) was performed with flow cytometry. This study reported that the combination of Phyllanthus niruri L formula with toman fish albumin (PNA) and Phyllanthus urinaria L formula with toman fish albumin (PUA) was able to show striking hepatoprotective effects through a significant decrease in SGOT-SGPT levels in the blood of male Rattus norvegicus and decreased proinflammatory cytokine profiles in Rattus norvegicus liver cells males exposed to CCl4. In addition, the antioxidant defenses of PNA and PUA formulas almost completely prevent the occurrence of degeneration, necrosis, fibrosis and steatosis in liver cells. So that the combination of PNA and PUA formulas given has the potential to be used as an alternative to hepatitis drugs. (shrink)

We propose to study the wound healing in Zebrafish by using firstly a differential approach for modelling morphogens diffusion and cell chemotactic motion, and secondly a hybrid model of tissue regeneration, where cells are considered as individual objects and molecular concentrations are described by partial differential equations.

Chronic wounds, such as diabetic foot ulcers, pose significant challenges due to their prolonged inflammation state, slow vascularization, lack of supportive matrix, and frequent recurrence. Biocompatible materials like silk fibroin (SF) and collagen can be promising in chronic wound healing applications due to their biocompatibility, and ability to act as supporting matrix necessary for tissue regeneration. This study explores the development and characterization of SF-based biomaterials in various formats, including gels, lyophilized scaffolds, and films, by combining them with (...) collagen (Col) and heparin (Hep) molecules that are known for the wound-healing properties. SF gels, films, and lyophilized scaffolds were characterized for water retention capacity, porosity, contact angle, and antibacterial properties. Curcumin-loaded films reported moderate wetting behavior but were brittle, thin and hard. Freeze-dried scaffolds possessed higher water retention capacity compared to the sonicated gels and films, and showed a porous network structure, while the fabricated SF gels disintegrated in water. SF with a chelating agent demonstrated mild antibacterial properties, which were retained when combined with Collagen peptides and Heparin. The antimicrobial effect was significantly enhanced when SF+Col+Hep was added with antimicrobial agents such as Gentamicin and Ceftriaxone. The study concludes that SF-based scaffolds, particularly those incorporating collagen peptides and heparin, can be leveraged for molecular delivery application towards wound healing. Future research should focus on improving mechanical properties, measuring release kinetics of heparin and other biomolecules from SF-based lyophilized scaffolds, and conducting in vivo studies to validate the therapeutic value. (shrink)

A prominent view on personal identity over time, Jeff McMahan’s ‘Embodied Mind Account’ (2002) holds that we cease to exist only once our brains can no longer sustain the basic capacity to uphold consciousness. One of the many implications of this view on identity persistence is that we continue to exist throughout even the most severe cases of dementia, until our consciousness irreversibly shuts down. In this paper, I argue that, while the most convincing of prominent accounts of personal identity (...) over time, McMahan’s account faces serious challenges in explanatory power of dementias and related neurodegenerative conditions. Particularly, this becomes visible in the face of emerging methods for neural tissue regeneration, and the possibility of ‘re-emerging patients’. I argue that medical professionals’ neglecting qualitative aspects of identity risks resulting in grave misunderstandings in decision-making processes, and ethically objectionable outcomes in future practices. Finally, I propose revisions which could potentially salvage the great benefits that Embodied Mind Theory still can bring to the field of dementia care in terms of understanding life, death, and identity across the lifespan. (shrink)

In Europe ≈15,000 patients receive larval therapy for wound treatment annually. Over the past few years, clinical studies have demonstrated the success of larvae of Lucilia sericata as debridement agents. This is based on a combination of physical and biochemical actions. Laboratory investigations have advanced our understanding of the biochemical mechanisms underlying the beneficial effects of larval secretions, including removal of dead tissue, reduction of the bacterial burden, and promotion of tissue regeneration. The present article summarizes our (...) current understanding of the microbiological, immunological, and wound healing actions of larval therapy, and the molecules involved in these beneficial effects. Future studies will focus on the isolation, identification, and (pre)clinical testing of the effective molecules of L. sericata larvae. These molecules may be candidates for the development of new agents for the treatment of several infectious and inflammatory diseases, including chronic wounds. (shrink)

Epigenetic control of gene expression by chromatin remodeling is critical for adult stem cell function. A decline in stem cell function is observed during aging, which is accompanied by changes in the chromatin structure that are currently unexplained. Here, we hypothesize that these epigenetic changes originate from the limited cellular capability to inherit epigenetic information. We suggest that spontaneous loss of histone modification, due to fluctuations over short time scales, gives rise to long‐term changes in DNA methylation and, accordingly, in (...) gene expression. These changes are assumed to impair stem cell function and, thus, to contribute to aging. We discuss cell replication as a major source of fluctuations in histone modification patterns. Gene silencing by our proposed mechanism can be interpreted as a manifestation of the conflict between the stem cell plasticity required for tissue regeneration and the permanent silencing of potentially deleterious genomic sequences. (shrink)

The study of cellular senescence and proliferative lifespan is becoming increasingly important because of the promises of autologous cell therapy, the need for model systems for tissue disease and the implication of senescent cell phenotypes in organismal disease states such as sarcopenia, diabetes and various cancers, among others. Here, we explain the concepts of proliferative cellular lifespan and cellular senescence, and we present factors that have been shown to mediate cellular lifespan positively or negatively. We review much recent literature (...) and present potential molecular mechanisms by which lifespan mediation occurs, drawing from the fields of telomere biology, metabolism, NAD+ and sirtuin biology, growth factor signaling and oxygen and antioxidants. We conclude that cellular lifespan and senescence are complex concepts that are governed by multiple independent and interdependent pathways, and that greater understanding of these pathways, their interactions and their convergence upon specific cellular phenotypes may lead to viable therapies for tissue regeneration and treatment of age‐related pathologies, which are caused by or exacerbated by senescent cells in vivo. (shrink)

Bone marrow is the main site for hematopoiesis in adults. It acts as a niche for hematopoietic stem cells (HSCs) and contains non‐hematopoietic cells that contribute to stem cell dormancy, quiescence, self‐renewal, and differentiation. HSC also exist in resting spleen of several species, although their contribution to hematopoiesis under steady‐state conditions is unknown. The spleen can however undergo extramedullary hematopoiesis (EMH) triggered by physiological stress or disease. With the loss of bone marrow niches in aging and disease, the spleen as (...) an alternative tissue site for hematopoiesis is an important consideration for future therapy, particularly during HSC transplantation. In terms of harnessing the spleen as a site for hematopoiesis, here the remarkable regenerative capacity of the spleen is considered with a view to forming additional or ectopic spleen tissue through cell engraftment. Studies in mice indicate the potential for such grafts to support the influx of hematopoietic cells leading to the development of normal spleen architecture. An important goal will be the formation of functional ectopic spleen tissue as an aid to hematopoietic recovery following clinical treatments that impact bone marrow. For example, expansion or replacement of niches could be considered where myeloablation ahead of HSC transplantation compromises treatment outcomes. (shrink)

Many animals display a capacity to regenerate tissues or even a complete body. One of the main goals of regenerative biology is to identify the genes and genetic networks necessary for this process. Drosophila offers an ideal model system for such studies. The wide range of genetic and genomic approaches available for use in flies has helped in initiating the deciphering of the mechanisms underlying regeneration, and the results may be applicable to other organisms, including mammals. Moreover, most models (...) of regeneration require experimental manipulation, whereas in Drosophila discrete domains can be ablated by genetically induced methods. Here, we present a summary of current research into imaginal disc regeneration and discuss the power of this tissue as a tool for understanding the genetics of regeneration. (shrink)

In three recent articles it was shown that β‐catenin is crucial for the establishment and the maintenance of the overall polarity and especially for the character ‘posterior’ in planarians. If the transcription of the β‐catenin gene was silenced by RNA interference, the overall polarity is lost, and in regenerating fragments a posterior blastema displays anterior characters by forming eyes and anterior ganglia. An attempt is made to integrate these new data, well‐known older observations, and observations from other regenerating systems into (...) an outline of a model that will clarify our current understanding as well as highlight areas still to be developed. (shrink)

The paper addresses the formation of striking patterns within originally near-homogenous tissue, the process prototypical for embryology, and represented in particularly purist form by cut sections of hydra regenerating, by internal reorganisation of the pre-existing tissue, a complete animal with head and foot. The essential requirements are autocatalytic, self-enhancing activation, combined with inhibitory or depletion effects of wider range – “lateral inhibition”. Not only de-novo-pattern formation, but also well known, striking features of developmental regulation such as induction, inhibition, (...) and proportion regulation can be explained on this basis. The theory provides a mathematical recipe for the construction of molecular models with criteria for the necessary non-linear interactions. It has since been widely applied to different developmental processes. (shrink)

Development of methods to reawaken the semi‐dormant regenerative potential that lies within adult human tissues would hold promise for the restoration of diseased or damaged organs and tissues. While most of the regeneration potential is suppressed in many vertebrates, including humans, during adult life, urodele amphibians (salamanders) retain their regenerative ability throughout adulthood. Studies in newts and axolotls, two salamander models, have provided significant knowledge about adult limb regeneration. In this review, we present a comparative analysis of salamander (...) and mammalian regeneration and discuss how evolutionarily altered properties of the regenerative environment can be exploited to restore full regenerative potential in the human body. (shrink)

Cells can transit between a range of stable epithelial and mesenchymal states and this has allowed the evolution of complex body forms. Epithelial to mesenchymal transition (EMT) and its reverse, mesenchymal to epithelial transition (MET), occur sequentially in development and organogenesis. EMT often accompanies transitions between stem‐like cells and their more differentiated progeny, as occurs at gastrulation, although the relevance of this had not been clarified. New findings from the cancer and cell reprogramming fields suggest that EMT and MET can (...) act as essential portals to stem cell character. Here, we review these findings in the broader context of EMT and MET with emphasis on stem cell biology. Using the heart as an example, we also explore the potential role of EMT/MET in organ regeneration. Understanding EMT and MET at a network level will give us new tools to probe stem cell character and enhance tissue repair. (shrink)

The introductory personal remarks refer to my motivations for choosing research projects, and for moving from physics to molecular biology and then to development, with Hydra as a model system. Historically, Trembley’s discovery of Hydra regeneration in 1744 was the begin¬ning of developmental biology as we understand it, with passionate debates about preformation versus de novo generation, mechanisms versus organisms. In fact, seemingly conflicting bottom-up and top-down concepts are both required in combination to understand development. In modern terms, this (...) means analysing the molecules involved, as well as searching for physical principles underlying development within systems of molecules, cells and tissues. During the last decade, molecular biology has provided surprising and impressive evidence that the same types of mol¬ecules and molecular systems are involved in pattern formation in a wide range of organisms, including coelenterates like Hydra, and thus appear to have been “invented” early in evolution. Likewise, the features of certain systems, especially those of developmental regulation, are found in many different organisms. This includes the generation of spatial structures by the interplay of self-enhancing activation and “lateral” inhibitory effects of wider range, which is a main topic of my essay. Hydra regeneration is a particularly clear model for the formation of defined patterns within initially near-uniform tissues. In conclusion, this essay emphasizes the analysis of development in terms of physical laws, including the application of mathematics, and insists that Hydra was, and will continue to be, a rewarding model for understanding general features of embryogenesis and regeneration. -/- -/- . (shrink)

For nearly two centuries, developmental biologists have known that body organs are derived from distinct germ layers. They have argued that adult stem cells formed in one of these, mesoderm for example, cannot give rise to cells that originate in another. We disagree. An exception to this “rule” has been described in crayfish recently. In this species, hemocytes appear to replenish neurogenic cells. This may happen in humans as well. In women who were given male bone marrow‐derived cells, Y chromosome (...) positive cheek cells and brain neurons were detected. While repopulation of these tissues by bone marrow derived cells may not occur normally, and while it does not appear to be terribly efficient, the phenomenon should be studied in more detail. Perhaps cells in the marrow could be used to regenerate tissues elsewhere. (shrink)

How epithelial tissues are able to self-renew to maintain homeostasis and regenerate in response to injury remains a persistent question. The transcriptional effectors YAP and TAZ are increasingly being recognized as central mediators of epithelial stem cell biology, and a wealth of recent studies have been directed at understanding the control and activity of these factors. Recent work by Hu et al. has added to this knowledge, as they identify an Integrin-FAK-CDC42-PP1A signaling cascade that directs nuclear YAP/TAZ activity in stem (...) cell populations of the mouse incisor, and define convergence on mTORC1 signaling as an important mediator of the proliferation of these cells. Here, we review recent studies on YAP/TAZ function and regulation in epithelial tissue-specific stem cells, merging the Hu et al. study together with our current knowledge of YAP/TAZ. The Hippo pathway effectors YAP and TAZ broadly regulate adult stem cells, and have recently been implicated in dental epithelial stem cell proliferation and restricted differentiation via an Integrin-FAK-CDC42-PP1A cascade. Here, we discuss the extracellular cues which control YAP/TAZ activity and examine downstream pathways that direct stem cell fate. (shrink)

: Stem cell research that requires the destruction of human embryos is incompatible with Catholic moral principles, and with any ethic that gives serious weight to the moral status of the human embryo. Moreover, because there are promising and morally acceptable alternative approaches to the repair and regeneration of human tissues, and because treatments that rely on destruction of human embryos would be morally offensive to many patients, embryonic stem cell research may play a far less significant role in (...) medical progress than proponents believe. (shrink)

Significant progress in the molecular investigation of endogenous bioelectric signals during pattern formation in growing tissues has been enabled by recently developed techniques. Ion flows and voltage gradients produced by ion channels and pumps are key regulators of cell proliferation, migration, and differentiation. Now, instructive roles for bioelectrical gradients in embryogenesis, regeneration, and neoplasm are being revealed through the use of fluorescent voltage reporters and functional experiments using well‐characterized channel mutants. Transmembrane voltage gradients (Vmem) determine anatomical polarity and function (...) as master regulators during appendage regeneration and embryonic left‐right patterning. A state‐of‐the‐art recent study reveals that they can also serve as prepatterns for gene expression domains during craniofacial patterning. Continued development of novel tools and better ways to think about physical controls of cell‐cell interactions will lead to mastery of the morphogenetic information stored in physiological networks. This will enable fundamental advances in basic understanding of growth and form, as well as transformative biomedical applications in regenerative medicine. (shrink)

This article considers the role of the adult epithelial stem cell, with particular reference to the intestinal epithelial stem cell. Although the potential of adult stem cells has been revealed in a number of recent publications, the organization and control of the stem cell hierarchy in epithelial tissues is still not fully understood. The intestinal epithelium is an excellent model in which to study such hierarchies, having a distinctive polarity and high rate of cell proliferation and migration. Studies on the (...) small intestinal crypt provide insight into the characteristics of the stem cells in normal and regenerating circumstances and demonstrate why a thorough understanding of these cells is an essential pre‐requisite for stem cell based therapeutic approaches. BioEssays 24:91–98, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

After a long and successful career in tracheal surgery and lung cancer, Paolo Macchiarini became very famous in 2008 with the transplantation of a trachea from a cadaver that then apparently used the patient’s own stem cells to supposedly regenerate new trachea, i.e., tissue-engineered tracheae. Among the nine patients that received this revolutionary treatment, using biological or artificial tracheae, under Macchiarini’s supervision, six have reportedly died. Although several critics had expressed concerns with the procedures, allegations of misconduct against Macchiarini (...) first arose in August of 2014 by four Karolinska Institutet (KI) colleagues, and an independent investigation was called for by KI based on claims made in seven published papers. Among the claims were the fact that the procedure constituted a high risk, information on the patients was incomplete and that there was no or incomplete ethical approval, thus constituting misconduct. His CV was also shown to contain inaccuracies. By September 10, 2016, most of these claims have now proved to be true, and Macchiarini was found guilty of misconduct by KI. This paper looks primarily at earlier published papers by Macchiarini and his collaborators in a search for clues to better understand the evolution of altruism, or narcissism. An assessment of the controversial papers, and of letters written by critics and skeptics like Pierre R. Delaere, indicate that insufficient experimental evidence was presented for several case studies, and that claims made about the success of the procedures exceeded what was shown by the evidence. A domino effect of personal and professional tragedies ensued, in rapid succession, between 2014 and 2016. The effect on the field of stem cell research has been chilling, and the side-effects have taken their toll, with several high-profile resignations, primarily at KI, within the Swedish education system and in the Nobel Committee. This case has mesmerized the bioethics and biomedical communities for years. (shrink)

This article addresses some critical aspects of the relationship between aesthetic medicine (AM) and ethics and proposes a possible deontological ethical line to pursue based on current practices. The role of AM has always been controversial and suffers from unclear practical and moral boundaries, even within academic settings, since it aims to improve the appearance of individuals, not to cure a disease. Today, it is essential and pertinent to discuss these issues, as AM specialists are dealing with a growing and (...) increasingly demanding patient population that has undergone profound evolution in recent years. Current challenges within the field of AM include a lack of global uniformity concerning the education of AM specialists, an increasing number of physicians practicing AM with diverse training backgrounds, the spread of AM being practiced outside of medical practice or hospital settings, and the influence of social media where the success is modelled and dictated by the identification of a youthful appearance). By the field of action enriched by technologies that aim not only at enhancement per se but also at the preservation and regeneration of tissues, it is necessary to establish an active multidisciplinary discussion on the definition of shared ethical limits. This discussion would allow AM to fully reclaim its identity as a specialty that aims to improve patient well-being whilst maintaining respect for patient aesthetic harmony, the expertise of specialists who practice AM, the essential role of safety, and awareness of the importance of a confidential doctor−patient relationship. (shrink)

The ability to manipulate embryonic stem cells for tissues and organs regeneration and the great expectation existing in cellular therapy have lead to drive the attention of not only scientists but also philosophers and theologists on the issue of >. In this paper this issue is delt with from a gnoseologic perspective.

Both blood vessels and nerves are guided to their target. Vascular endothelial growth factor (VEGF)A is a key signal in the induction of vessel growth (a process termed angiogenesis). Though initial studies, now a decade ago, indicated that VEGF is an endothelial cell‐specific factor, more recent findings revealed that VEGF also has direct effects on neural cells. Genetic studies showed that mice with reduced VEGF levels develop adult‐onset motor neuron degeneration, reminiscent of the human neurodegenerative disorder amyotrophic lateral sclerosis (ALS). (...) Additional genetic studies confirmed that VEGF is a modifier of motor neuron degeneration in humans and in SOD1G93A mice—a model of ALS. Reduced VEGF levels may promote motor neuron degeneration by limiting neural tissue perfusion and VEGF‐dependent neuroprotection. VEGF also affects neuron death after acute spinal cord or cerebral ischemia, and has also been implicated in other neurological disorders such as diabetic and ischemic neuropathy, nerve regeneration, Parkinson's disease, Alzheimer's disease and multiple sclerosis. These findings have raised growing interest in assessing the therapeutic potential of VEGF for neurodegenerative disorders. BioEssays 26:943–954, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:BOOK REVIEWS 733 The Giving and Taking of Life: Essays Ethical. By JAMES TUNSTEAD BURTCHAELL. Notre Dame, Indiana: University of Notre Dame Press, 1989. xiv + 304 pp. $29.95. One looks forward to the writings of James Burtchaell not only because his judgments are almost always on the side of the angels hut also because his mastery of the English language often enables him to say in a few (...) words what writers of lesser skill say in volumes. This is a collection of previously-published essays on a wide range of topics including contraception, abortion, the use of biotechnology in human reproduction, the use of fetal tissue in medical therapy, law in a pluralist society, liberation theology, the morality of terrorism and the relationship of religion to politics. In its own way, this hook poses well the moral questions of how we and " nature " are to relate to the newly emerging generation of technology. Because the articles are so diverse, it is not possible to give a detailed account or critique of each of them, and rather than doing that I will focus attention only on the issue of ethics and the newly emerging technology which will have a profound impact on not only our personal lives, hut also our society and politics. And to an even greater extent, newly emerging technological developments will have an enormous impact on the way in which our race regenerates and orients itself in the future. On a case-by-case basis, Burtchaell raises these issues with great force and clarity, even though his understanding of nature and technology is not entirely clear. He suggests that nature is far more subtle and vital than we commonly assume and that it has its own ways of fighting hack against our technological assaults against it. Our attempts to control and manipulate nature through technological means provide nature with an opportunity to protect itself hy striking hack at us in ways previously unimagined. Using technology to bend nature to our will is much like the Australian Aborigine who vainly tried to throw away his boomerang! What is most striking about this hook is the contradictory way in which Burtchaell employs the concept of nature to determine the morality of certain enterprises. This contradiction is seen most clearly hy comparing his assessments of artificial contraception and technological transmission of human life. The contrast is so sharp that the issue of the foundations of his thought can he called into question. When one compares his favorable assessment of artificial contraception to his critical evaluation of technological reproduction of human life, one wonders if there is an underlying principle guiding his moral deliberations or whether it is merely his intuitions, likes and dislikes (strongly 734 BOOK REVIEWS colored and shaped by his cultural setting) that determine his evaluations. In "'Human Life' and Human Love", Burtchaell vigorously criticizes the substance, form and arguments of the encyclical Humanae Vitae. For him, the great flaw in this encyclical was the weight it gave to the distinction between natural and artificial contraception and the absolute condemnation visited upon the latter. Seeing little difference between more natural methods of contraception like natural family planning and the use of the pill, Burtchaell argues that artificial contraception should have been given some kind of moral permissibility by Pope Paul VI (P. 99). But it is not clear why he gives limited support to artificial birth control after one reads his harsh criticisms of it: But the venture of technology overshot its original goals in several unforeseen ways. America now has the highest rate of teenage pregnancy in what we like to call the developed world. The incidence of sexual prom· iscuity, venereal disease, abortion, marital collapse, fatherless children, child abuse and abandonment, wanton breeding by the thriftless (and dusky) poor is probably higher than at any time in our national history. The founders [Margaret Sanger and Marie Stopes] did concede that their program might not immediately achieve its desired results. But that was because of the lack, in their time, of an ' ideal ' contraceptive. Its development was to be expected from further assiduous scientific research. Seventy years and much assiduous research later, the same message is still... (shrink)

Cet ouvrage veut montrer la grande affinité entre la révélation Muhammadienne et la pensée française. La Révélation veut nous révéler à nous-même, notre propre esprit. L'esprit a une patrie, il s'incarne dans un certain paysage terrestre. Naître ce n'est pas apparaître avec un corps en un certain endroit du monde. Naître c'est s'éprouver dans une certaine ambiance du savoir et de la sensibilité, dans une langue, dans un tissu d'impressions qualitatives qu'on appelle une culture. Si l'Islam bien compris peut être (...) pour la France une source de régénération, le génie intellectuel français peut, à son tour, donner à l'Islam une toute nouvelle lecture de ses fondements. L'injonction première donnée au Prophète fut "Iqrâ" : "Lis!" La grande pensée française peut nous apprendre à lire autrement la révélation divine. "Nous avons fait de vous des nations et des tribus, pour que vous vous entreconnaissiez" (Coran, 49 : 13). (shrink)

The Cnidaria represent the most ancient eumetazoan phylum. Members of this group possess typical animal cells and tissues such as sensory cells, nerve cells, muscle cells and epithelia. Due to their unique phylogenetic position, cnidarians have traditionally been used as a reference group in various comparative studies. We propose the colonial marine hydroid, Hydractinia, as a convenient, versatile platform for basic and applied research in developmental biology, reproduction, immunology, environmental studies and more. In addition to being a typical cnidarian representative, (...) Hydractinia offers many practical and theoretical advantages: studies that are feasible in Hydra like regeneration, pattern regulation, and cell renewal from stem cells, can be supplemented by genetic analyses and classical embryology in Hydractinia. Metamorphosis of the planula larva of Hydractinia can be used as a model for cell activation and communication and the presence of a genetically controlled allorecognition system makes it a suitable model for comparative immunology. Most importantly, Hydractinia may be manipulated at most aspects of its (short) life cycle. It has already been the subject of many studies in various disciplines, some of which are discussed in this essay. BioEssays 23:963–971, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

In spite of the advances in our knowledge of cancer biology, most cancers remain not curable with present therapies. Current treatments consider cancer as resulting from uncontrolled proliferation and are non‐specific. Although they can reduce tumour burden, relapse occurs in most cases. This was long attributed to incomplete tumour elimination, but recent developments indicate that different types of cells contribute to the tumour structure, and that the tumour's cellular organization would be analogous to that of a normal tissue, with (...) a main mass of differentiating cells sensitive to anti proliferative agents, together with a small percentage of quiescent, resistant stem cells responsible for replenishing the tumour: the Cancer Stem Cells (CSCs). Anti‐CSCs targeted therapeutic agents would prevent tumour regeneration. New mouse models tailored to exploit this novel concept will be critical to develop CSC‐based anti‐cancer therapies. Here we review the biological basis and the therapeutic implications of the stem‐cell model of cancer. BioEssays 29:1269–1280, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

When two populations of cells within a tissue mass differ from one another in magnitude or type of intercellular adhesions, a boundary can form within the tissue, across which cells will fail to mix. This phenomenon may occur regardless of the identity of the molecules that mediate cell adhesion. If, in addition, a choice between the two adhesive states is regulated by a molecule the concentration of which is periodic in space, or in time, then alternating bands of (...) non‐mixing tissue, or segments, can form. But temporal or spatial periodicities in concentration will tend to arise for any molecule that is positively autoregu‐latory. It is therefore proposed that segmentation is a ‘generic’ property of metazoan organisms, and that metamerism would be expected to have emerged numerous times during evolution. A simple model of segmentation, based solely on differential adhesion and periodic regulation of adhesion, can account for segment properties as disparate as those seen in long and short germ band insects, and for diverse experimental results on boundary regeneration in the chick hind brain and the insect cuticle. It is suggested that the complex, multicom‐ponent segment‐forming systems found in contemporary organisms (e.g., Drosophila) are the products of evolutionary recruitment of molecular cues such as homeobox gene products, that increase the reliability and stability of metameric patterns originally templated by generic self‐organizing properties of tissues. (shrink)

Much of the current research in regenerative medicine concentrates on stem-cell therapy that exploits the regenerative capacities of stem cells when injected into different types of human tissues. Although new therapeutic paths have been opened up by induced pluripotent cells and human mesenchymal cells, the rate of success is still low and mainly due to the difficulties of managing cell proliferation and differentiation, giving rise to non-controlled stem cell differentiation that ultimately leads to cancer. Despite being still far from becoming (...) a reality, these studies highlight the role of physical and biological constraints (e.g., cues and morphogenetic fields) placed by tissue microenvironment on stem cell fate. This asks for a clarification of the coupling of stem cells and microenvironmental factors in regenerative medicine. We argue that extracellular matrix and stem cells have a causal reciprocal and asymmetric relationship in that the 3D organization and composition of the extracellular matrix establish a spatial, temporal, and mechanical control over the fate of stem cells, which enable them to interact and control (as well as be controlled by) the cellular components and soluble factors of microenvironment. Such an account clarifies the notions of stemness and stem cell regeneration consistently with that of microenvironment. (shrink)

The vertebrate eye lens has been used extensively as a model for developmental processes such as determination, embryonic induction, cellular differentiation, transdifferentiation and regeneration, with the crystallin genes being a prime example of developmentally controlled, tissue‐preferred gene expression. Recent studies have shown that Pax‐6, a transcription factor containing both a paired domain and homeodomain, is a key protein regulating lens determination and crystallin gene expression in the lens. The use of Pax‐6 for expression of different crystallin genes provides (...) a new link at the developmental and transcriptional level among the diverse crystallins and may lead to new insights into their evolutionary recruitment as refractive proteins. (shrink)