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)

In this essay, I will try to elaborate the fundamental postulates of transdifferential ontology, developed through the inscription of some basic concepts of poststructuralist philosophy within the realm of general system theory. In this manner, a system/being will be conceptualized as set of elements which is organized as a functional whole, whose goal is not to establish a homeostasis but to menage and organize disruptive forces of lack/surplus, that represents non-mediated kernel of any system. Therefore, any system is fundamentally grounded (...) on imbalance and radical incompleteness as inherent conditions of its possibility. Among different kind of systems, the complex self - organizing systems based on feedback loops are governed by the principle of syntropy and its transdifferential organization of reality. In order to explicate the syntropic movement of systems, the concept of signifier is expanded beyond the boundaries of language, and the process of writing, as a permanent invention of in-vent, is interpreted in the manner of never ending sublation of the system and subversion of the subject. The interconnection between the general system theory and poststructuralist philosophy will provide us with a conceptual apparatus which overcomes both linguistic and entropic limitations of above mentioned domains, in order to conceive, interpret, predict and govern processes of becoming on different levels of organization of systems. (shrink)

The use of a reporter gene in transgenic mice indicates that there are many local mutations and large genomic rearrangements per somatic cell that accumulate with age at different rates per organ and without visible effects. Dissociation of the cells for monolayer culture brings out great heterogeneity of size and loss of function among cells that presumably reflect genetic and epigenetic differences among the cells, but are masked in organized tissue. The regulatory power of a mass of contiguous normal cells (...) is expressed in its capacity to normalize the appearance and growth behavior of solitary homophilic neoplastic cells, and to redirect differentiation of solitary heterophilic stem‐like cells. Intimate contact between the interacting cells is required to induce these changes. The normalization of the neoplastic phenotype does not require gap junctional communication between cells, though transdifferentiation might. These varied relationships are manifestations of the unifying biological principle of “order in the large over heterogeneity in the small”. BioEssays 28: 515–524, 2006. © 2006 Wiley Periodicals, Inc. (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)

Endothelial cells line the inside of all blood vessels, forming a structurally and functionally heterogenous population of cells. Their complexity and diversity has long been recognized, yet very little is known about the molecules and regulatory mechanisms that mediate the heterogeneity of different endothelial cell populations. The constitutive organ‐ and microenvironment‐specific phenotype of endothelial cells controls internal body compartmentation, regulating the trafficking of circulating cells to distinct vascular beds. In contrast, surface molecules associated with the activated cytokine‐inducible endothelial phenotype play (...) a critical role in pathological conditions including inflammation, tumor angiogenesis, and wound healing. Differentiation of the endothelial cell phenotypes appears to follow similar mechanisms to the differentiation of hematopoietic cells, with the exception that endothelial cells maintain transdifferentiating competence. The present review offers a scheme of endothelial cell differentially expressed endothelial cell molecules as targets for directed therapeutic intervention. (shrink)

Cells in the basal metazoan phylum Cnidaria are characterized by remarkable plasticity in their differentiation capacity. The mechanism controlling asymmetric cell divisions is not understood in cnidarians or in any other animal group. PIWI proteins recently have been shown to be involved in maintaining the self‐renewal capacity of stem cells in organisms as diverse as ciliates, flies, worms and mammals. Seipel et al.1 find that, in the cnidarian Podocoryne carnea, the Piwi homolog Cniwi is transcriptionally upregulated when the polyp generates (...) buds, which will develop into medusae. Since transdifferentiation of striated muscle cells to smooth muscle cells also activated Cniwi expression, Cniwi appears to play a crucial role in differentiation events. The discovery should facilitate elucidation of the poorly understood factors that control asymmetric cell divisions at the beginning of animal evolution. BioEssays 26:929–931, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Rejuvenation of cells by reprogramming toward the pluripotent state raises increasing attention. In fact, generation of induced pluripotent stem cells (iPSCs) completely reverses age‐associated molecular features, including elongation of telomeres, resetting of epigenetic clocks and age‐associated transcriptomic changes, and even evasion of replicative senescence. However, reprogramming into iPSCs also entails complete de‐differentiation with loss of cellular identity, as well as the risk of teratoma formation in anti‐ageing treatment paradigms. Recent studies indicate that partial reprogramming by limited exposure to reprogramming factors (...) can reset epigenetic ageing clocks while maintaining cellular identity. So far, there is no commonly accepted definition of partial reprogramming, which is alternatively called interrupted reprogramming, and it remains to be elucidated how the process can be controlled and if it resembles a stable intermediate state. In this review, we discuss if the rejuvenation program can be uncoupled from the pluripotency program or if ageing and cell fate determination are inextricably linked. Alternative rejuvenation approaches with reprogramming into a pluripotent state, partial reprogramming, transdifferentiation, and the possibility of selective resetting of cellular clocks are also discussed. (shrink)

The retina pigment epithelium (RPE) is a highly specialised epithelium that serves as a multifunctional and indispensable component of the vertebrate eye. Although a great deal of attention has been paid to its transdifferentiation capabilities and its ancillary functions in neural retina development, little is known about the molecular mechanisms that specify the RPE itself. Recent advances in our understanding of the genetic network that controls the progressive specification of the eye anlage in vertebrates have provided some of the (...) initial cues to the mechanisms responsible for RPE patterning. Here, we have outlined many recent findings that suggest that a limited number of transcription factors, including Otx2, Mitf and Pax6 and a few signalling cascades, are the elements required for the onset of RPE specification in vertebrates. Furthermore, using this information and the data available on the specification of the pigmented cells of primitive chordates, we have ventured some hypotheses on the origin of RPE cells during evolution. BioEssays 26:766–777, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Technologies for deriving human neurons in vitro have transformed our ability to study cellular and molecular components of human neurotransmission. Three groups, including our own, have recently published methods for efficiently generating human serotonergic neurons in vitro. Remarkably, serotonergic neurons derived from each method robustly produce serotonin, express raphe genes, are electrically active, and respond to selective serotonin reuptake inhibitors in vitro. Two of the methods utilize transdifferentiation technology by overexpressing key serotonergic transcription factors. The third and most recent (...) method involves differentiating induced pluripotent stem cells (iPSCs) to serotonergic neurons using developmental patterning cues. In this mini‐review, we briefly describe the developmental programs governing serotonergic specification in vivo and how they have been harnessed to achieve serotonergic differentiation in vitro. We discuss the distinct and overlapping features of the recently published methodologies and their value in the context of in vitro disease modeling.Also see the video abstract here. (shrink)

Testis determination in most mammals is regulated by a genetic hierarchy initiated by the SRY gene. Early ovarian development has long been thought of as a default pathway switched on passively by the absence of SRY. Recent studies challenge this view and show that the ovary constantly represses male‐specific genes, from embryonic stages to adulthood. Notably, the absence of the crucial ovarian transcription factor FOXL2 (alone or in combination with other factors) induces a derepression of male‐specific genes during development, postnatally (...) and, even more interestingly, during adulthood. Strikingly, in the adult, targeted ablation of Foxl2 leads to a molecular transdifferentiation of the supporting cells of the ovary, which acquire cytological and transcriptomic characteristics of the supporting cells of the testes. These studies bring many answers to the field of gonadal determination, differentiation and maintenance, but also open many questions. (shrink)

This paper aims to clarify the consequences of new scientific and philosophical approaches for the practical-theoretical framework of modern developmental biology. I highlight normal development, and the instructive-permissive distinction, as key parts of this framework which shape how variation is conceptualised and managed. Furthermore, I establish the different dimensions of biological variation: the units, temporality and mode of variation. Using the analytical frame established by this, I interpret a selection of examples as challenges to the instructive-permissive distinction. These examples include (...) the phenomena of developmental plasticity and transdifferentiation, the role of the microbiome in development, and new methodological approaches to standardisation and the assessment of causes. Furthermore, I argue that investigations into organismal development should investigate the effects of a wider range of kinds of variation including variation in the units, modes and temporalities of development. I close by examining various possible opportunities for producing and using normal development free of the assumptions of the instructive-permissive distinction. These opportunities are afforded by recent developments, which include new ways of producing standards incorporating more natural variation and being based on function rather than structure, and the ability to produce, store, and process large quantities of data. (shrink)

This article is concerned with the problem of the relation between the genetic information contained in the DNA and the emergence of visible structure in multicellular animals. The answer is sought in a reappraisal of the data of experimental embryology, considering molecular, cellular and organismal aspects. The presence of specific molecules only confers a tissue identity on the cells when their concentration exceeds the threshold of differentiation. When this condition is not fulfilled the activity of the genes that code for (...) the specific molecules in question only confers on them a histogenetic potency, i.e. the capacity to form the corresponding tissue in further development (or to transdifferentiate to that tissue). The progressive restriction of histogenetic potencies during development reflects the irreversible repression of more and more genes. The establishment of a given tissue identity under the influence of an inducing tissue (or a morphogenetic hormone) is only possible when the cells have acquired the competence to respond. Tissue differentiation proceeds progressively during development thanks to the cytoplasmic memory that cells retain collectively (or sometimes individually) of the items of information successively registered by their ancestors cells. The increasing complexity of visible structure emerging during development results only from the progression of tissue differentiation. This involves continual exchange of information among the cells and leads to (1) cell displacements and rearrangements, particularly during organogenesis and (2) extreme diversification of cell individualities within tissues, particularly during postembryonic growth. A mutation (just as a teratogenic factor) evokes an anomaly that is localized in both space and time because it alters a certain aspect of cell behaviour (particularly cell surface adhesiveness or mitotic activity) at the time when this is involved in the establishment of a particular structural trait. Neither the organization of the adult nor the modalities of development are encoded in the DNA. The automatic concatenation of cell interactions in the embryo and the structural amplification it entails is conditioned by the specific biochemical composition of the cytoplasm of the egg and by the heterogeneous distribution of its inclusions. (shrink)

The principles of automation in animal development, as previously inferred from the concept of Cell Sociology do not fit in well with the current concept of sequential gene derepression. A more adequate explanation for those principles has been found in the literature dealing with the biochemical aspects of differentiation. Since oocytes and embryonic cells contain a greater variety of mRNAs than differentiated cells, as well as many tissue-specific (luxury) substances, it is concluded that the diversification of tissues consists of a (...) progressive selection of specific metabolic strategies, mediated by cell-to-cell contacts, from a broad range of pre-existing strategies. For each tissue, prior to its final determination, one luxury metabolic strategy is progressively intensified and becomes dominant. The others are either suppressed or maintained as latent metabolic strategies. The latter may on occasion become dominant again (transdifferentiation). These phenomena require a theory which considers gene regulation as the activation of otherwise repressed genes by specific activator RNAs. The high (apparently maximal) transcriptional activity on the lampbrush chromosomes may represent the synthesis of all the kinds of activator RNAs which are required for the reactivation of the genes during early development. A general conception is propounded of the automatism and programming of animal development, as inferred from the confrontation of these ideas with the concept of Cell Sociology. (shrink)

Cell therapy means treating diseases with the body's own cells. One of the cell types most in demand for therapeutic purposes is the pancreatic β‐cell. This is because diabetes is one of the major healthcare problems in the world. Diabetes can be treated by islet transplantation but the major limitation is the shortage of organ donors. To overcome the shortfall in donors, alternative sources of pancreatic β‐cells must be found. Potential sources include embryonic or adult stem cells or, from existing (...) β‐cells. There is now a startling new addition to this list of therapies: the pancreatic α‐cell. Thorel and colleagues recently showed that under circumstances of extreme pancreatic β‐cell loss, α‐cells may serve to replenish the insulin‐producing compartment. This conversion of α‐cells to β‐cells represents an example of transdifferentiation. Understanding the molecular basis for transdifferentiation may help to enhance the generation of β‐cells for the treatment of diabetes. (shrink)

We recently discovered a novel subset of beta cells that resemble immature beta cells during pancreas development. We named these “virgin” beta cells as they do not stem from existing mature beta cells. Virgin beta cells are found exclusively at the islet periphery in areas that we therefore designated as the “neogenic niche.” As beta cells are our only source of insulin, their loss leads to diabetes. Islets also contain glucagon‐producing alpha cells and somatostatin‐producing delta cells, that are important for (...) glucose homeostasis and form a mantle surrounding the beta cell core. This 3D architecture is important and determines access to blood flow and innervation. We propose that the distinctive islet architecture may also play an important, but hitherto unappreciated role in generation of new endocrine cells, including beta cells. We discuss several predictions to further test the contribution of the neogenic niche to beta cell regeneration. (shrink)

Organisms must adapt to environmental stresses to ensure their survival and prosperity. Different types of stresses, including thermal, mechanical, and hypoxic stresses, can alter the cellular state that accompanies changes in gene expression but not the cellular identity determined by a chromatin state that remains stable throughout life. Some tissues, such as adipose tissue, demonstrate remarkable plasticity and adaptability in response to environmental cues, enabling reversible cellular identity changes; however, the mechanisms underlying these changes are not well understood. We hypothesized (...) that positive and/or negative “Integrators” sense environmental cues and coordinate the epigenetic and transcriptional pathways required for changes in cellular identity. Adverse environmental factors such as pollution disrupt the coordinated control contributing to disease development. Further research based on this hypothesis will reveal how organisms adapt to fluctuating environmental conditions, such as temperature, extracellular matrix stiffness, oxygen, cytokines, and hormonal cues by changing their cellular identities. (shrink)

The application of in vivo genetic lineage tracing has advanced our understanding of cellular mechanisms for tissue renewal in organs with slow turnover, like the lung. These studies have identified an adult stem cell with very different properties than classically understood ones that maintain continuously cycling tissues such as the intestine. A portrait has emerged of an ensemble of cellular programs that replenish the cells that line the gas exchange (alveolar) surface, enabling a response tailored to the extent of cell (...) loss. A capacity for differentiated cells to undergo direct lineage transitions allows for local restoration of proper cell balance at sites of injury. We present these recent findings as a paradigm for how a relatively quiescent tissue compartment can maintain homeostasis throughout a lifetime punctuated by injuries ranging from mild to life‐threatening, and discuss how dysfunction or insufficiency of alveolar repair programs produce serious health consequences like cancer and fibrosis. (shrink)