T‐lymphocyte recognition, activation and function involve anumber of T‐cell‐specific surface proteins in addition to the receptor for antigen. The structure, function and genetic analysis of four of these T‐cell differentiation antigens are discussed.

Proto‐oncogene products may be multi‐functional proteins with various roles in cell differentiation as well as cell proliferation. The molecular biology of the gene products of three well characterized proto‐oncogenes (c‐fos, c‐myc and c‐src) are described, and the roles of three other proto‐oncogene products, involved in hormone and growth factor reception, are reviewed.

Mast cells are a unique class of blood cell. Unlike most blood cells, undifferentiated precursors of mast cells migrate in the bloodstream, invade tissues, proliferate there and then differentiate. Even after differentiation, some mast cells may proliferate extensively. Differentiation of mast cells is regulated by both diffusible growth factors and direct contact with fibroblasts.

The paper is devoted to modelling of cell differentiation in an initially homogeneous cell population. The mechanism which provides coexistence of two cell lineages in the initially homogeneous cell population is suggested. If cell differentiation is initiated locally in space in the population of undifferentiated cells, it can propagate as a travelling wave converting undifferentiated cells into differentiated ones. We suggest a model of this process which takes into account intracellular regulation, extracellular regulation (...) and different cell types. They include undifferentiated cells and two types of differentiated cells. When a cell differentiates, its choice between two types of differentiated cells is determined by the concentrations of intracellular proteins. Differentiated cells can either stimulate differentiation into their own cell lineage or into another cell lineage. In the case of the positive feedback, only one lineage of differentiated cells will finally appear. In the case of negative feedback, both of them can coexist. In this case a periodic spatial pattern emerges behind the wave. (shrink)

Leydig cells, traditionally known as the steroidogenic workhorses of the testis, are now known to synthesize significant amounts of non‐steroid products including some potent bioactive proteins and peptides. These products are currently being investigated for their potential role in the paracrine regulation of spermatogenesis in the nearby seminiferous tubules and in the autocrine regulation of Leydig cell function.

T‐bet and Eomes are two related transcription factors (TFs) that regulate the differentiation of cytotoxic lymphocytes such as Natural Killer (NK) cells and CD8 T cells. Recent genome‐wide analyses suggest they have complementary roles in instructing the transcriptional program of NK cells, although their DNA binding sites appear to be very similar. In this essay, we discuss the mechanisms that could specify their action, addressing their expression profile, the cofactors they interact with, as well as their roles in the (...) epigenetic regulation of chromatin accessibility. Based on the recent literature on these TFs, we propose different models to describe how they regulate gene expression in NK cells at steady state, or in the context of activation or exhaustion. We also discuss recent findings in the field of CD8 T cell differentiation and residency, where Eomes and T‐bet appear to be major regulators, and the parallels that can be drawn between mechanisms of NK and CD8 T cell differentiation and trafficking. (shrink)

From stem cells to oocyte, Drosophila germ cells undergo a short, defined lineage. Molecular genetic analyses of a collection of female sterile mutations have indicated that a germ cell‐specific organelle called the fusome has a central role at several steps in this lineage. The fusome grows from a prominent spherical organelle to an elongated and branched structure that connects all mitotic sisters in a germ cell syncytium. The organelle is assembled from proteins normally found in the membrane skeleton (...) and, additionally, contains an extensive membranous reticulum, the probable product of differentiation‐dependent vesicle trafficking. This review briefly summarizes a current view of the processes that drive germ cell differentiation, particularly the various roles that the fusome might play in regulating the developmental events. Future efforts will consider to what extent an organelle assembly‐dependent model for differentiation is heuristic and whether the Drosophila fusome represents a homolog of a similar organelle in vertebrate lymphocytes. (shrink)

Mouse embryonic stem cells have an unlimited lifespan in cultures if they are prevented from differentiating. After differentiating, they produce cells which divide only a limited number of times. These changes seen in cultures parallel events that occur in the developing embryo, where immortal embryonic cells differentiate and produce mortal somatic ones. The data strongly suggest that differentiation initiates senescence, but this view entails additional assumptions in order to explain how the highly differentiated sexual gametes manage to remain potentially (...) immortal. Cells differentiate by blocking expression from large parts of their genome and it is suggested that losses or gains of genetic totipotency determine cellular lifespans. Cells destined to be somatic do not regain totipotency and senesce, while germ‐line cells regain complete genome expression and immortality after meiosis and gamete fusions. Losses of genetic totipotency could induce senescence by lowering the levels of repair and maintenance enzymes. (shrink)

For over a century, Haeckel's Gastraea theory remained a dominant theory to explain the origin of multicellular animals. According to this theory, the animal ancestor was a blastula‐like colony of uniform cells that gradually evolved cell differentiation. Today, however, genes that typically control metazoan development, cell differentiation, cell‐to‐cell adhesion, and cell‐to‐matrix adhesion are found in various unicellular relatives of the Metazoa, which suggests the origin of the genetic programs of cell differentiation (...) and adhesion in the root of the Opisthokonta. Multicellular stages occurring in the complex life cycles of opisthokont protists (mesomycetozoeans and choanoflagellates) never resemble a blastula. Here, we discuss a more realistic scenario of transition to multicellularity through integration of pre‐existing transient cell types into the body of an early metazoon, which possessed a complex life cycle with a differentiated sedentary filter‐feeding trophic stage and a non‐feeding blastula‐like larva, the synzoospore. Choanoflagellates are considered as forms with secondarily simplified life cycles. (shrink)

Hepatocellular carcinoma represents the third leading cause of cancer-related death. Because HCC is multicentric with time, excluding the few transplanted patients, sooner or later it becomes untreatable with loco-regional therapies and, until some years ago, it was not responsive to systemic therapies. In 2005 a randomized trial indicated the efficacy of a product containing stem cell differentiation stage factors taken from zebrafish embryos during the stage in which the totipotent stem cells are differentiating into the pluripotent adult stem (...) cells. In such a trial the patients, with “intermediate” and “advanced” HCC according to Barcelona Clinic Liver Cancer/American Association for the Study of Liver Diseases guidelines, presented benefit in terms of performance status and objective tumoral response, with some cases of complete response, that is, sustained disappearance of the neoplastic areas or blood supply therein, accompanied by normalization of alpha-fetoprotein... (shrink)

The stable differentiation of cells into other cell types typically involves dramatic reorganization of cellular structures and functions. This often includes remodeling of the cell cycle and the apparatus that controls it. Here we review our understanding of the role and regulation of cell cycle control elements during cell differentiation in the yeast, Saccharomyces cerevisiae. Although the process of differentiation may be more overtly obvious in metazoan organisms, those systems are by nature more (...) difficult to study at a mechanistic level. We consider the relatively well‐understood mechanisms by which mating‐type switching and the pheromone‐induced differentiation of gametes are coupled to the cell cycle as well as the more obscure mechanisms that govern the remodeling of the cell cycle during meiosis and filamentous growth. In some cases, the cell cycle is a primary stimulus for differentiation whereas, in other cases, the signals that promote differentiation alter the cell cycle. Thus, despite relative simplicity of these processes in yeast, the nature of the interplay between the cell cycle and differentiation is diverse. BioEssays 25:856–867, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Pluripotency can be considered a functional characteristic of pluripotent stem cells (PSCs) populations and their niches, rather than a property of individual cells. In this view, individual cells within the population independently adopt a variety of different expression states, maintained by different signaling, transcriptional, and epigenetics regulatory networks. In this review, we propose that generation of integrative network models from single cell data will be essential for getting a better understanding of the regulation of self‐renewal and differentiation. In (...) particular, we suggest that the identification of network stability determinants in these integrative models will provide important insights into the mechanisms mediating the transduction of signals from the niche, and how these signals can trigger differentiation. In this regard, the differential use of these stability determinants in subpopulation‐specific regulatory networks would mediate differentiation into different cell fates. We suggest that this approach could offer a promising avenue for the development of novel strategies for increasing the efficiency and fidelity of differentiation, which could have a strong impact on regenerative medicine. (shrink)

On the basis of the evidence that tumor development is suppressed by the embryonic microenvironment, some experiments using the factors taken from Zebrafish embryo at precise stages of cell differentiation were made. These experiments demonstrated a significant growth inhibition on different tumor cell lines in vitro. The observed mechanism of tumor growth inhibition is connected with the key-role cell cycle regulation molecules, such as p53 and pRb, which are modified by transcriptional or post-translational processes. Research on (...) apoptosis and differentiation revealed that treatment with these factors induces caspase-3 with a p73 apoptotic-dependent pathway activation and a concurrent significant normalization of e-cadherin and beta-catenin ratio. Other experiments found a synergistic effect on the colon cancer proliferation curve after the concurrent treatment with these factors and 5-fluorouracil. Finally, a product prepared for human therapy demonstrated 19.8% regression and 16% stable disease in an... (shrink)

Recent research highlights that inflammatory signaling pathways such as pattern recognition receptor (PRR) signaling and inflammatory cytokine signaling play an important role in both on‐demand hematopoiesis as well as steady‐state hematopoiesis. Knockout studies have demonstrated the necessity of several distinct pathways in these processes, but often lack information about the contribution of specific cell types to the phenotypes in question. Transplantation studies have increased the resolution to the level of specific cell types by testing the necessity of inflammatory (...) pathways specifically in donor hematopoietic stem and progenitor cells (HSPCs) or in recipient niche cells. Here, we argue that for an integrated understanding of how these processes occur in vivo and to inform the development of therapies that modulate hematopoietic responses, we need studies that knockout inflammatory signaling receptors in a cell‐specific manner and compare the phenotypes caused by knockout in individual niche cells versus HSPCs. (shrink)

The KCTD family includes tetramerization (T1) domain containing proteins with diverse biological effects. We identified a novel member of the KCTD family, BTBD10. A comprehensive analysis of protein‐protein interactions (PPIs) allowed us to put forth a number of testable hypotheses concerning the biological functions for individual KCTD proteins. In particular, we predict that KCTD20 participates in the AKT‐mTOR‐p70 S6k signaling cascade, KCTD5 plays a role in cytokinesis in a NEK6 and ch‐TOG‐dependent manner, KCTD10 regulates the RhoA/RhoB pathway. Developmental regulator KCTD15 (...) represses AP‐2α and contributes to energy homeostasis by suppressing early adipogenesis. TNFAIP1‐like KCTD proteins may participate in post‐replication DNA repair through PCNA ubiquitination. KCTD12 may suppress the proliferation of gastrointestinal cells through interference with GABAb signaling. KCTD9 deserves experimental attention as the only eukaryotic protein with a DNA‐like pentapeptide repeat domain. The value of manual curation of PPIs and analysis of existing high‐throughput data should not be underestimated. (shrink)

Central to the differentiation and patterning of the Drosophila oocyte is the asymmetric intracellular localization of numerous mRNA and protein molecules involved in developmental signalling. Recent advances have identified some of the molecules mediating oocyte differentiation, specification of the anterior pole of the embryo, and determination of the embryonic germ line. This work is considered in the context of the classical model of the germ plasm as a cytoplasmic determinant for germ cell formation.

This article concerns the elaboration of epigenetic models for differentiation. I discuss how results and conclusions arising from studies of prokaryotes were extrapolated to explain differentiation during metazoan development. In this respect, I focus on the presentation of a multi-stable biochemical model by Delbrück in 1949, and on a series of works dealing with enzyme adaptation in Escherichia coli that culminated in Jacob and Monod's operon model. These influential contributions are discussed in the context of debates on nuclear (...) versus cytoplasmic heredity, on the regulation of gene expression, as well as on the mechanisms at the basis of cell differentiation. (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)

Cellular pattern formations of some epithelia are believed to be governed by the direct lateral inhibition rule of cell differentiation. That is, initially equivalent cells are all competent to differentiate, but once a cell has differentiated, the cell inhibits its immediate neighbors from following this pathway. Such a differentiation repeats until all non-inhibited cells have differentiated. The cellular polygonal patterns can be characterized by the numbers of undifferentiated cells and differentiated ones. When the differentiated cells (...) become large in size, the polygonal pattern is deformed since more cells are needed to enclose the large cell. An actual example of such a cellular pattern was examined. The pupal wing epidermis of a butterfly Pieris rapae shows a transition of the equivalent-size cell pattern to the pattern involving large cells. The process of the transition was analyzed by using the method of weighted Voronoi tessellation that is useful for treatment of irregularly sized polygons. The analysis supported that the pattern transition of the early stage of the pupal wing epidermis is governed by the lateral inhibition rule. The differentiation takes place in order of largeness, but not smallness, of the apical polygonal area in the differentiating region of the pupal wing. (shrink)

Development and maintenance of diverse organ systems require context‐specific regulation of stem cell behaviour. We hypothesize that this is achieved via reciprocal regulation between the cell cycle machinery and differentiation factors. This idea is supported by the parallel evolutionary emergence of differentiation pathways, cell cycle components and complex multicellularity. In addition, the activities of different cell cycle phases have been found to bias cells towards stem cell maintenance or differentiation. Finally, several direct (...) mechanistic links between these two processes have been established. Here, we focus on interactions between cyclin‐CDK complexes and differentiation regulators of the Notch pathway and Sox family of transcription factors within the context of pluripotent and neural stem cells. Thus, this hypothesis formalizes the links between these two processes as an integrated network. Since such factors are common to all stem cells, better understanding their interconnections will help to explain their behaviour in health and disease. (shrink)

Honey bees are eusocial insects and the workers inform their nestmates of information regarding the location of food source using symbolic communication, called ‘dance communication’, that are based on their highly advanced learning abilities. Mushroom bodies (MBs), a higher-order center in the honey bee brain, comprise some subtypes/populations of interneurons termed Kenyon cells (KCs) that are distinguished by their cell body size and location in the MBs, as well as their gene expression profiles. Although the role of MBs in (...) learning ability has been studied extensively in the honey bee, the roles of each KC subtype and their evolution in hymenopteran insects remain mostly unknown. This mini-review describes recent progress in the analysis of gene/protein expression profiles and possible functions of KC subtypes/populations in the honey bee. Especially, the discovery of novel KC subtype/population, ‘middle-type KCs’ and ‘KC population expressing FoxP’, necessitated a redefinition of the KC subtype/population. Analysis of the effects of inhibiting gene function in a KC subtype-preferential manner revealed the function of the gene product as well as of the subtype where it is expressed. Genes expressed in a KC subtype/population-preferential manner can be used to trace the differentiation of KC subtypes during the honey bee ontogeny and the possible evolution of KC subtypes in hymenopteran insects. Current findings suggest that the three KC subtypes are unique characteristics to the aculeate hymenopteran insects. Finally, recent application of genome editing for the study of KC subtype functions in the honey bee is described. Genes expressed in a KC subtype-preferential manner can be good candidate target genes for genome editing, because they are likely related to highly advanced brain functions and some of them are dispensable for normal development and sexual maturation in honey bees. (shrink)

How cell commitment and differentiation are controlled in the early stages of embryogenesis is a problem that has long fascinated developmental biologists. Retinoic acidinduced differentiation of embryonal carcinoma cells in culture provides a model in which these questions can be explored. Recent work has yielded exciting insights into the central series of molecular changes which drives the commitment of these cells to formation of a new phenotype. Interacting with the key molecules in this central pathway is a (...) variety of transcription factors, many of which show changes in availability and/or activity during differentiation. In various combinations, these modulate the activities of genes involved in both cell proliferation and in the production of extracellular matrix and other proteins characteristic of differentiated cells. (shrink)

In this paper we develop a differential analogue of o-minimal cell decomposition for the theory CODF of closed ordered differential fields. Thanks to this differential cell decomposition we define a well-behaving dimension function on the class of definable sets in CODF. We conclude this paper by proving that this dimension is closely related to both the usual differential transcendence degree and the topological dimension associated, in this case, with a natural differential topology on ordered differential fields.

We review recent progress in the stem cell biology of the respiratory system, and discuss its scientific and translational ramifications. Several studies have defined novel stem cells in postnatal lung and airways and implicated their roles in tissue homeostasis and repair. In addition, significant advances in the generation of respiratory epithelium from pluripotent stem cells (PSCs) now provide a novel and powerful platform for understanding lung development, modeling pulmonary diseases, and implementing drug screening. Finally, breakthroughs have been made in (...) the generation of decellularized lung matrices that can serve as a scaffold for repopulation with respiratory cells derived from either postnatal or PSCs. These studies are a critical step forward towards the still distant goal of stem cell‐based regenerative medicine for diseases of lung and airways. (shrink)

The mechanism(s) by which the thymidine analogue 5‐bromodeoxyuridine (BUdR) specifically inhibits the expression of differentiated functions is poorly understood, as are the ways in which cells regulate processes exhibiting probabilistic aspects. I have developed a theoretical model for the regulation of the decision of myogenic cells to differentiate that can explain both of the above phenomena. This model provided a strategy for isolating myoblast variants that had amplified the expression of the factors regulating the decision to differentiate. These myoblasts served (...) as the source of mRNA for making and screening a cDNA library in order to isolate these factors. The successful cloning of these genes should represent a major advance in our understanding of the molecular basis for the major coordinated changes in gene expression that accompany cell differentiation. (shrink)

Self‐renewal and differentiation of stem cells are tightly regulated processes subject to intrinsic and extrinsic signals. Molecular chaperones and co‐chaperones, especially heat shock proteins (Hsp), are ubiquitous molecules involved in the modulation of protein conformational and complexation states. The function of Hsp, which are typically associated with stress response and tolerance, is well characterized in differentiated cells, while their role in stem cells remains unclear. It appears that embryonic stem cells exhibit increased stress tolerance and concomitant high levels of (...) chaperone expression. This review critically evaluates stem cell research from a molecular chaperone perspective. Furthermore, we propose a model of chaperone‐modulated self‐renewal in mouse embryonic stem cells. (shrink)

Balancing self‐renewal and differentiation of stem cells is an important issue in stem cell and cancer biology. Recently, the Drosophila neuroblast (NB), neural stem cell has emerged as an excellent model for stem cell self‐renewal and tumorigenesis. It is of great interest to understand how defects in the asymmetric division of neural stem cells lead to tumor formation. Here, we review recent advances in asymmetric division and the self‐renewal control of Drosophila NBs. We summarize molecular mechanisms (...) of asymmetric cell division and discuss how the defects in asymmetric division lead to tumor formation. Gain‐of‐function or loss‐of‐function of various proteins in the asymmetric machinery can drive NB overgrowth and tumor formation. These proteins control either the asymmetric protein localization or mitotic spindle orientation of NBs. We also discuss other mechanisms of brain tumor suppression that are beyond the control of asymmetric division. (shrink)

Mitochondrial shape change, brought about by molecules that promote either fission or fusion between individual mitochondria, has been documented in several model systems. However, the deeper significance of mitochondrial shape change has only recently begun to emerge: among others, it appears to play a role in the regulation of cell proliferation. Here, I review the emerging interplay between mitochondrial fission‐fusion components with cell cycle regulatory machineries and how that may impact cell differentiation. Regulation of mitochondrial shape (...) may modulate mitochondrial metabolism and/or energetics to promote crosstalk between signaling components and the cell cycle machinery. Focused research in this area will reveal the exact role of mitochondria in development and disease, specifically in stem cell regulation and tumorigenesis. Such research may also reveal whether and how the endosymbiotic event that gave rise to the mitochondrion was crucial for the evolution of cell cycle regulatory mechanisms in eukaryotes that are absent in prokaryotes. (shrink)

Cell lines and cell samples from patients provide opportunities for studying the mechanisms of leukemic cellular differentiation and proliferation. Phorbol esters and 1,25 dihydroxy vitamin D3 can induce differentiation of myeloid leukemic cells to macrophages. Differentiation to granulocytes can be induced by several different compounds. Myeloid differentiation is associated closely with the alteration in expression of several oncogenes. These regulatory events may be associated with the extent of methylation, unfolding or association of chromatin to (...) the nuclear matrix. Oncogene amplification, mutation, or deletion can occur with malignant transformation. Future studies point to the development of specific pharmacological agents which can modify the neoplastic transformation. (shrink)

The transcription of rat prolactin and growth hormone genes in vitro requires a pituitary transcription factor, specific to certain cell types in the pituitary, which currently appears to be the PUF‐I/Pit‐1/GHF‐1 protein. This factor binds to cis‐regulatory elements in the 5′ region of both genes and exerts a positive influence on transcription initiation presumably by interacting with general transcription factors. The PUF‐I/Pit‐1/GHF‐1 transcriptional regulatory protein probably has an important role in not only the differentiation of the pituitary lactotroph/somatotroph (...) cell lineage; it is also expressed in the early development of the nervous system but its function there is less well documented. It appears to be one member of a family of trans‐activator proteins involved in differential gene expression in several cell types. (shrink)

In [T. Brihaye, C. Michaux, C. Rivière, Cell decomposition and dimension function in the theory of closed ordered differential fields, Ann. Pure Appl. Logic .] the authors proved a cell decomposition theorem for the theory of closed ordered differential fields which generalizes the usual Cell Decomposition Theorem for o-minimal structures. As a consequence of this result, a well-behaving dimension function on definable sets in CODF was introduced. Here we continue the study of this cell decomposition in (...) CODF by proving three additional results. We first discuss the relation between the δ-cells introduced in the above-mentioned reference and the notion of Kolchin polynomial in differential algebra. We then prove two generalizations of classical decomposition theorems in o-minimal structures. More exactly we give a theorem of decomposition into definably d-connected components and a differential cell decomposition theorem for a particular class of definable functions in CODF. (shrink)

The study of haemopoiesis enables us to address one of the central questions of developmental biology, concerning the molecular mechanisms by which a multipotent cell develops into distinct differentiated progeny. Recent work(1) suggests specific roles for retinoic acid receptors at two distinct stages of haemopoiesis. Continuous cell lines of lymphohaemopoietic progenitors were established by infection with a retrovirus containing a dominant negative retinoic acid receptor. The cell lines depend on stem cell factor for their proliferation and (...) can be induced to diffentiate into B‐lymphocytes, erythrocytes, neutrophils, monocytes, mast cells and megakaryocytes. Since lymphohaemopoietic progenitors represent less than 0.01% of nucleated marrow cells, immortalised progenitors provide a valuable system with which to study haemopoiesis on a molecular level. (shrink)

The repertoire of acceptor glycoproteins for concanavalin A expressed by a cultured tumour cell reflects the normal developmental lineage from which it was derived, as well as the degree of maturation along that lineage. Antibodies to this particular set of glycoproteins show a considerable specificity towards normal differentiation antigens which are often preferentially associated with the less mature intermediates of the corresponding pathway. In addition, comparisons between ‘immature’ and ‘mature’ tumour cells can be used to identify glycoproteins associated (...) with specific differentiated functions such as secretion. Thus tumour cell glycoproteins provide useful probes for analysis of the molecular biology of development and differentiation. (shrink)

Many lymphokine genes have now been cloned from activated T cells and their products have been expressed in mammalian cells. Use of these recombinant lymphokines has provided the opportunity to evaluate both the spectrum of their biological activities and the mechanisms of their action in promoting proliferation and differentiation of hemopoietic and lymphoid cells. Characterization of the structure of lymphokine genes will provide information about their regulated expression in T‐cell activation.

Imagine cells that live in a high‐gradient magnetic field (HGMF). Through what mechanisms do the cells sense a non‐uniform magnetic field and how such a field changes the cell fate? We show that magnetic forces generated by HGMFs can be comparable to intracellular forces and therefore may be capable of altering the functionality of an individual cell and tissues in unprecedented ways. We identify the cellular effectors of such fields and propose novel routes in cell biology predicting (...) new biological effects such as magnetic control of cell‐to‐cell communication and vesicle transport, magnetic control of intracellular ROS levels, magnetically induced differentiation of stem cells, magnetically assisted cell division, or prevention of cells from dividing. On the basis of experimental facts and theoretical modeling we reveal timescales of cellular responses to high‐gradient magnetic fields and suggest an explicit dependence of the cell response time on the magnitude of the magnetic field gradient. (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)

Recent work by Magnuson, Solomon and Grossman(1) adds to a growing body of evidence indicating that microorganisms possess sophisticated signaling systems that enable them to sense and respond to environmental challenges. Typically, this response results in morphological, physiological and even genetic differentiation, paralleling that observed among higher organisms. These signaling systems may be interpreted as adaptations that maximize the reproductive potential of a population.

Cognition or higher brain activity is sometimes seen as a phenomenon greater than the sum of its parts. This viewpoint however is largely dependent on the state of the art of experimental techniques that endeavor to characterize morphology and its association to function. Retinal ganglion cells are readily accessible for this work and we discuss recent advances in computational techniques in identifying novel parameters that describe structural attributes possibly associated with specific function. These parameters are based on calculating wavelet gradients (...) from cell images followed by the extraction of meaningful measures including 2nd wavelet moment, entropy of orientation, and curvature. For the three cell types analyzed, the mean 2nd wavelet moment, which relates to the field of influence of the dendritic-tree segments was significantly different. cells had the highest mean 2nd wavelet moment, followed by the and cells (134 ± 22, 93 ± 19 and 63 ± 12, respectively). There was no significant difference between cells for entropy of orientation, indicating no class with a preferential orientation of their dendritic tree. Curvature provided similar results to the 2nd wavelet moment with cells having the highest curvature followed by and the cells (mean ± SD: 161 ± 15; 134 ± 22; 121 ± 15). Our feature space analysis also indicated a difference between these cell types. No difference was found between the and cell types and their physiological counterparts the Y and X cells based on wavelet analysis. Both the X and Y cells can be divided into two subtypes, the ON- and OFF-center cells based on the stratification level of the dendritic tree within the retina. Using 2nd wavelet moment, a difference in their morphological attributes, not reported previously, was noted for these subtypes. The 2nd wavelet moment and curvature are further discussed with respect to explaining regularity of spacing and coverage associated with retinal ganglion cell mosaics. (shrink)

Recently it has become clear that integrins and other adhesive receptors play an important role in the control of cell growth and differentiation. In various cell types, anchorage to the extracellular matrix via integrins strongly influences the ability of the cell to respond to soluble mitogens or to differentiation factors. Thus adhesive receptors must generate signals that influence cell behavior. Some of the pathways of adhesion receptor signaling are now beginning to be worked out, (...) but there is still much to learn. In particular, the mechanistic basis for the cooperation between anchorage signals and signals from soluble growth and differentiation factors remains ill‐defined. This review will examine some of the current information linking adhesion receptors to control of mitogenesis and differentiation. (shrink)