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Results for “cell fate plasticity”

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PubMed2003

Untangling the functional potential of PSA-NCAM-expressing cells in CNS development and brain repair strategies.

Central nervous system (CNS) neural stem cells (NSCs), which are mostly defined by their ability to self-renew and to generate the three main cell lineages of the CNS, were isolated from discrete regions of the adult mammalian CNS including the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus in the hippocampus. At early stages of CNS cell fate determination, NSCs give rise to progenitors that express the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). PSA-NCAM(+) cells persist in adult brain regions where neuronal plasticity and sustained formation of new neurons occur. PSA-NCAM has been shown to be involved in the regulation of CNS myelination as well as in changes of cell morphology that are necessary for motility, axonal guidance, synapse formation, and functional plasticity in the CNS. Although being preferentially committed to a restricted either glial or neuronal fate, cultured PSA-NCAM(plus) progenitors do preserve a relative degree of multipotentiality. Considering that PSA-NCAM(+) cells can be neatly used for brain repair purposes, there is much interest for studying signaling factors regulating their development. With this regard, it is noteworthy that neurotransmitters, which belong to the micro-environment of neural cells in vivo, regulate morphogenetic events preceding synaptogenesis such as cell proliferation, migration, differentiation and death. Consistently, several ionotropic but also G-protein-coupled neurotransmitter receptors were found to be expressed in CNS embryonic and postnatal progenitors. In the present review, we outlined the ins and outs of PSA-NCAM(plus) cells addressing to what extent our understanding of extrinsic and in particular neurotransmitter-mediated signaling in these CNS precursor cells might represent a new leading track to develop alternative strategies to stimulate brain repair.

Animals↗

PubMed2006

Functional characterization of cell hybrids generated by induced fusion of primary porcine mesenchymal stem cells with an immortal murine cell line.

Bone marrow mesenchymal stem cells (MSC) integrate into various organs and contribute to the regeneration of diverse tissues. However, the mechanistic basis of the plasticity of MSC is not fully understood. The change of cell fate has been suggested to occur through cell fusion. We have generated hybrid cell lines by polyethylene-glycol-mediated cell fusion of primary porcine MSC with the immortal murine fibroblast cell line F7, a derivative of the GM05267 cell line. The hybrid cell lines display fibroblastic morphology and proliferate like immortal cells. They contain tetraploid to hexaploid porcine chromosomes accompanied by hypo-diploid murine chromosomes. Interestingly, many hybrid cell lines also express high levels of tissue-nonspecific alkaline phosphatase, which is considered to be a marker of undifferentiated embryonic stem cells. All tested hybrid cell lines retain osteogenic differentiation, a few of them also retain adipogenic potential, but none retain chondrogenic differentiation. Conditioned media from hybrid cells enhance the proliferation of both early-passage and late-passage porcine MSC, indicating that the hybrid cells secrete diffusible growth stimulatory factors. Murine F7 cells thus have the unique property of generating immortal cell hybrids containing unusually high numbers of chromosomes derived from normal cells. These hybrid cells can be employed in various studies to improve our understanding of regenerative biology. This is the first report, to our knowledge, describing the generation of experimentally induced cell hybrids by using normal primary MSC.

Adipogenesis↗

PubMed2006

Signaling meets chromatin during tissue regeneration in Drosophila.

As transcription programs become stabilized in fate-determined cells by progressive patterning of chromatin structures, cells lose their plasticity and the ability to freely modify their identity in response to changing developmental cues. By contrast, stem cells maintain this flexibility, enabling them to embark on different determination pathways. However, regeneration of tissue requires an exception because determined cells are forced to switch their transcription programs to reconstruct the missing tissue. In Drosophila, proliferating cells in the regenerating imaginal discs can even switch to a new disc identity. New studies show that the increased plasticity observed during regeneration results from the action of multiple signaling pathways on chromatin malleability, cell-cycle profiles, and expression of 'stemness' genes. Understanding how signaling pathways can integrate to switch determined cells into multipotent cells has a great medical potential, especially in the field of tissue engineering and remodeling.

Animals↗

PubMed2007

Increased Notch 1 expression and attenuated stimulatory G protein coupling to adenylyl cyclase in osteonectin-null osteoblasts.

Osteonectin, or secreted protein acidic and rich in cysteine, is one of the most abundant noncollagen matrix components in bone. This matricellular protein regulates extracellular matrix assembly and maturation in addition to modulating cell behavior. Mice lacking osteonectin develop severe low-turnover osteopenia, and in vitro studies of osteonectin-null osteoblastic cells showed that osteonectin supports osteoblast formation, maturation, and survival. The present studies demonstrate that osteonectin-null osteoblastic cells have increased expression of Notch 1, a well-documented regulator of cell fate in multiple systems. Furthermore, osteonectin-null cells are more plastic and less committed to osteoblastic differentiation, able to pursue adipogenic differentiation given the appropriate signals. Notch 1 transcripts are down-regulated by inducers of cAMP in both wild-type and osteonectin-null osteoblasts, suggesting that the mutant osteoblasts may have a defect in generation of cAMP in response to stimuli. Indeed, many bone anabolic agents signal through increased cAMP. Wild-type and osteonectin-null osteoblasts generated comparable amounts of cAMP in response to forskolin, a direct stimulator of adenylyl cyclase. However, the ability of osteonectin-null osteoblasts to generate cAMP in response to cholera toxin, a direct stimulator of Gs, was attenuated. These data imply that osteonectin-null osteoblasts have decreased coupling of Gs to adenylyl cyclase. Because osteonectin promotes G protein coupling to an effector, our studies support the concept that low-turnover osteopenia can result from reducing G protein coupled receptor activity.

Adenylyl Cyclases↗

PubMed2001

Cell death in Tetrahymena thermophila: new observations on culture conditions.

We previously suggested that the cell fate of the protozoan ciliate, Tetrahymena thermophila, effectively relates to a quorum-sensing mechanism where cell-released factors support cell survival and proliferation. The cells have to be present above a critical initial density in a chemically defined nutrient medium in order to release a sufficient level of these factors to allow a new colony to flourish. At a relatively high rate of metabolism and/or macromolecular synthesis and below this critical density, cells began to die abruptly within 30 min of inoculation, and this death took the form of an explosive disintegration lasting less than 50 milliseconds. The cells died at any location in the culture, and the frequency of cell death was always lower in well-filled vials than those with medium/air interface. Cell death was inhibited by the addition of Actinomycin D or through modifications of the culture conditions either by reducing the oxygen tension or by decreasing the temperature of the growth medium. In addition, plastic caps in well-filled vials release substances, which promote cell survival. The fate of low-density cultures is related to certain 'physical' conditions, in addition to the availability of oxygen within closed culture systems.

Animals↗

PubMed1999

Early attempts at production of prawn cell lines.

This report describes some unsuccessful attempts to produce continuous cell lines from penaeid prawn tissues in the late 1980s. This information is presented so that others might save time by not repeating the unsuccessful measures that were attempted. The osmolarity of Penaeus monodon haemolymph was measured at 687 mOsmol/kg (N = 10). Of the media tested, the best medium for cell growth and maintenance was shown to be double strength L-15, supplemented with 10% foetal bovine serum, and 10% prawn muscle extract at 28 degrees C ( approximately 675.5 mOsmol/kg). Prawn muscle extract was made by homogenizing 30 g of prawn muscle in 50/50 ratio of distilled water/autoclaved seawater, clarified stepwise by centrifugation at 2k, 14k, 14k xg for 30 minutes each. The resultant supernatant was heat-inactivated on occasions with no improvement in growth. Preconditioned medium, cholesterol, galactose and trehalose supplements and the use of Cell-Tak did not improve growth conditions, and haemolymph extracts were detrimental to the cells. In addition it was shown that Nunc 25 cm(2) plastic culture flasks were better than Linbro and both were better than glass as substrates. The fate of 101 individual primary cell cultures, established from penaeid prawns, was as follows. Fifteen of the cultures succumbed to bacterial contamination, five became contaminated with fungi, four with thauastrochytrids, four succumbed to presumptive viral autocultures and two to ciliate contamination. Cell cultures derived from heart tissue could be maintained for a mean of 12.7 days (sd 9.7d), those derived from the epidermis 15.6 days (sd 9.0d), ovarian tissue 10 days (sd 2d), lymphoid organ 6.8 days (sd 0.4d), nerve cord and hepatopancreas 2 days. The most persistent cell cultures -- those derived from the heart explants -- contained dividing cells at 40 days, and epidermis cells were still dividing at 30 days. The longest lasting, non- proliferating, but viable, cell cultures were those of subcutis/epidermis and heart cells which remained viable for 240 and 307 days respectively. Only cell cultures from multiple prawns achieved 100% confluency in 25 cm(2) plastic culture flasks. No cultures survived attempts at passage by either trypsinisation or mechanical disruption with a rubber policeman. No cell lines were established.

Animals↗

PubMed2002

Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination.

On the basis of the ability of aggressive melanoma cells to participate in vasculogenic mimicry, particularly their expression of endothelial-associated genes, we examined the plasticity of human metastatic cutaneous melanoma cells with respect to vascular function. Fluorescently labeled metastatic melanoma cells were challenged to an ischemic microenvironment surgically induced in the hind limbs of nude mice. The data reveal the capability of these melanoma cells to express cell-fate determination molecules, normally expressed during embryonic vasculogenesis, and to participate in the neovascularization of circulation-deficient muscle. These results demonstrate the powerful influence of the microenvironment on the transendothelial differentiation of aggressive melanoma cells, and may provide new perspectives on tumor cell plasticity that could be exploited for novel therapeutic strategies.

Animals↗

PubMedDate not supplied

Neural development. FESN Study Group.

The FESN-sponsored follow-up meeting on neural development highlighted progress toward understanding several central issues in developmental neurobiology with particular emphasis on investigation into the mechanisms of cell fate determination. In systems as diverse as the HSN neurons of C. elegans, the photoreceptor cells of the Drosophila eye, the wide range of cell types within the vertebrate retina and the neurons of the cerebral cortex, hindbrain and spinal cord, the importance of environment in the determination and maintenance of cell fate was clearly established. Advances in cell marking techniques, including fluorescent dye and retroviral tagging, have enabled the fates of cells in normal and heterotypic environments to be followed and have demonstrated the initial plasticity of the progenitor cell population in many systems. The recent establishment of in vitro systems for studying neural development should further define the precise nature and identity of the environmental signals that act to establish and maintain cell fate. Of course, establishment of cell identity is only the initial phase in the formation of the mature nervous system. Once the fate of individual cells is determined, migration of cells to appropriate locations, extension of axons to appropriate targets and refinement of neuronal circuitry must occur. Both the definition of genes that influence these processes in nematodes and recent advances in imaging techniques that provide a means of observing these later, dynamic processes in 'living' brain slices promise to significantly advance understanding of the complexities of development of functional nervous systems.

Animals↗

PubMed2006

Implications of 'postmodern biology' for pathology: the Cell Doctrine.

Recent insights regarding stem cells, repression and de-repression of gene expression, and the application of Complexity Theory to cell and molecular biology require a re-evaluation of many long-held dogmas regarding the nature of the human body in health and disease. Greater than expected cell plasticity, trafficking of cells between organs, 'cellular uncertainty', stochasticity of cell origins and fates, and a reconsideration of Cell Doctrine itself all logically follow from these observations and conceptual approaches. In this paper, these themes will be considered and some implications for the investigative pathologist will be explored.

Cell Differentiation↗

PubMed2002

Differentiation plasticity of chondrocytes derived from mouse embryonic stem cells.

Evidence exists that cells of mesenchymal origin show a differentiation plasticity that depends on their differentiation state. We used in vitro differentiation of embryonic stem cells through embryoid bodies as a model to analyze chondrogenic and osteogenic differentiation because embryonic stem cells recapitulate early embryonic developmental phases during in vitro differentiation. Here, we show that embryonic stem cells differentiate into chondrocytes, which progressively develop into hypertrophic and calcifying cells. At a terminal differentiation stage, cells expressing an osteoblast-like phenotype appeared either by transdifferentiation from hypertrophic chondrocytes or directly from osteoblast precursor cells. Chondrocytes isolated from embryoid bodies initially dedifferentiated in culture but later re-expressed characteristics of mature chondrocytes. The process of redifferentiation was completely inhibited by transforming growth factor beta3. In clonal cultures of chondrocytes isolated from embryoid bodies, additional mesenchymal cell types expressing adipogenic properties were observed, which suggests that the subcultured chondrocytes indeed exhibit a certain differentiation plasticity. The clonal analysis confirmed that the chondrogenic cells change their developmental fate at least into the adipogenic lineage. In conclusion, we show that chondrocytic cells are able to transdifferentiate into other mesenchymal cells such as osteogenic and adipogenic cell types. These findings further strengthen the view that standardized selection strategies will be necessary to obtain defined cell populations for therapeutic applications.

Animals↗

PubMed1997

State of commitment of prospective neural plate and prospective mesoderm in late gastrula/early neurula stages of avian embryos.

We examined the ability of epiblast regions of known prospective fate from the late gastrula/early neurula stage of avian embryos to self-differentiate when placed heterotopically, testing their state of commitment. Three sites were examined: paranodal prospective neural plate ectoderm, containing cells fated to form a portion of the lateral wall of the neural tube at essentially all rostrocaudal levels of the neuraxis; prospective mesoderm from the caudolateral epiblast, containing cells fated to ingress through the primitive streak and to form lateral plate mesoderm; and prospective mesoderm from one level of the primitive streak, containing cells fated to continue ingressing and form paraxial mesoderm. Grafts from all sites exhibited plasticity. Grafts from the prospective neural plate ectoderm could readily substitute for regions of prospective mesoderm, when transplanted to either the epiblast or primitive streak, undergoing an epithelial-mesenchymal transition and, where appropriate, expressing paraxis, a gene expressed in paraxial mesoderm. Similarly, grafts containing prospective mesoderm from the epiblast could readily substitute for regions of the prospective neural plate ectoderm, undergoing convergent-extension movements characteristic of neuroectodermal cells and expressing appropriate genes such as Engrailed-2 and Hoxb-1. Grafts containing prospective mesoderm from the primitive streak could also incorporate into the neural plate and undergo convergence-extension movements of neurulation, although their principal contribution was to mesodermal and endodermal structures. Collectively, our results demonstrate that at the late gastrula/early neurula stage, germ layer-specific properties are not irrevocably fixed for prospective ectodermal and mesodermal regions of the blastoderm. Moreover, the signals responsible for the induction of these two tissue types must still be present and available at these late stages.

Animals↗

PubMed1989

Plasticity and differentiation of embryonic retinal cells after terminal mitosis.

The relation between terminal mitosis and the events that determine the developmental fate of embryonic precursor cells is not well understood. This relation has now been investigated with [3H]thymidine autoradiography to determine the time of cell birth and with a culture system that allows the testing of the developmental potential of cells isolated from the chick embryo retina. Contrary to the situation in vivo, where neuronal differentiation always precedes photoreceptor differentiation, photoreceptor differentiation occurs prematurely and precedes neuronal differentiation when precursor cells are isolated from the retina at early embryonic stages. Thus, cells born by embryonic day 5 (ED-5) give rise predominantly to photoreceptors when isolated for culture on ED-6 but develop mainly as neurons when isolated on ED-8. This suggests that retinal precursor cells retain after terminal mitosis the capacity to develop either as neurons or as photoreceptors. Moreover, photoreceptor differentiation appears to represent a constitutive or "default" pathway that precursor cells follow in the absence of neuron-inducing signals.

Animals↗

PubMed2006

Formation of neurons by non-neural adult stem cells: potential mechanism implicates an artifact of growth in culture.

Trans-differentiation is a mechanism proposed to explain how tissue-specific stem cells could generate cells of other organs, thus supporting the emerging concept of enhanced adult stem cell plasticity. Although spontaneous cell fusion rather than trans-differentiation may explain some unexpected cell fate changes in vivo, such a mechanism does not explain potential trans-differentiation events in vitro, including the generation of neural cell types from cultured bone marrow-derived stem cells. Here we present evidence that shows that cultured bone marrow-derived stem cells express neural proteins and form structures resembling neurons under defined growth conditions. We demonstrate that these changes in cell structure and neural protein expression are not consistent with typical neural development. Furthermore, the ability of bone marrow-derived stem cells to adopt a neural phenotype in vitro may occur as a result of cellular stress in response to removing cells from their niche and their growth in alternative environmental conditions. These findings suggest a potential explanation for the growth behavior of cultured bone marrow-derived stem cells and highlight the need to carefully validate the plasticity of stem cell differentiation.

Actins↗

PubMed1998

Globin gene expression is reprogrammed in chimeras generated by injecting adult hematopoietic stem cells into mouse blastocysts.

To elucidate whether the differentiation capacity of hematopoietic stem cells (HSCs) is influenced by specific microenvironments, adult mouse bone marrow-derived HSCs were injected into mouse blastocysts. Embryos developing from injected blastocysts contained donor-derived cells at various developmental stages, and progeny of the stem cells were detected in hematopoietic tissues. Thus, HSCs derived from an adult animal survive after injection into blastocysts and are able to participate in hematopoietic development. We further find that the erythroid progeny of transplanted adult HSCs express embryonic/fetal-type globin genes and, conversely, that embryonic and fetal progenitor cells transplanted into adult recipients transcribe the adult-type globin gene. Thus, the developmental potential of adult HSCs is evidently more plastic than previously thought, and the developmental stage of the hematopoietic microenvironment controls the developmental fate of transplanted progenitor cells.

Age Factors↗

PubMed1997

Emergence of determined myotome precursor cells in the somite.

Myotome and sclerotome precursor cells are derived, respectively, from cells in the dorsomedial and ventromedial regions of the somite. To assay changes in the specification of myotomal precursor cells during somite maturation, we implanted dorsomedial quadrant fragments, from staged quail somites, next to the notochords of host chick embryos, and superimposed two additional notochords on these implants. In this notochord signalling environment, dorsomedial quadrant cells that are developmentally plastic are expected to differentiate as cartilage, while cells determined to a myogenic fate are expected to differentiate as skeletal muscle. Large numbers of differentiated chondrocytes developed from dorsomedial quadrant grafts of all stages of paraxial mesoderm development tested, indicating that persistent chondrogenic potential in cells fated to form muscle and dermis can be elicited by notochord signals. Differentiated myocytes, however, appeared in two somite-stage-dependent phases. In the first phase, dorsomedial quadrants from segmental plate and early stage somites (II and IV) form small, disorganized clusters of individual myocytes. The frequency of first-phase myocluster formation increases as myogenic factor expression begins in the dorsomedial quadrant, indicating that myogenic determination assayed by this method is closely linked to the expression of myogenic factors in the dorsomedial quadrant. In the second phase, dorsomedial quadrants from somite stages XI-XIII consistently form morphologically organized muscle tissue containing large numbers of parallel-oriented, multinucleated myotubes. Mitotic labelling demonstrated that muscle precursors were determined to the muscle phenotype prior to withdrawal from the cell cycle. Thus, myogenic determination in cells of the dorsomedial quadrant is acquired at earlier stages of somite maturation than the ability to proliferate and form muscle tissue. These results are consistent with the hypothesis that successive lineages of myotome precursor cells with different mitotic and morphogenetic properties arise in the dorsomedial quadrant during somite maturation.

Animals↗

PubMed2001

Stem cells and aging: expanding the possibilities.

In the very early stages of embryonic development, cells have the capability of dividing indefinately and then differentiating into any type of cell in the body. Recent studies have revealed that much of this remarkable developmental potential of embryonic stem cells is retained by small populations of cells within most tissues in the adult. Intercellular signals that control the proliferation, differentiation and survival of stem cells are being identified and include a diverse array of growth factors, cytokines and cell adhesion molecules. Intracellular mechanisms that regulate stem cell fate are also emerging and include established second messenger pathways, novel transcription factors and telomerase. The possibility that a decline in the numbers or plasticity of stem cell populations contributes to aging and age-related disease is suggested by recent findings. The remarkable plasticity of stem cells suggests that endogenous or transplanted stem cells can be 'tweaked' in ways that will allow them to replace lost or dysfunctional cell populations in diseases ranging from neurodegenerative and hematopoietic disorders to diabetes and cardiovascular disease.

Aging↗

PubMed1998

Developmental fates of the mouse germ cell line.

The specification of mouse germ cell lineage takes place after a population of pluripotential cells is established, and cell communication among the pluripotential cells may be important for this process. Primordial germ cells (PGCs) first appear around the allantois at 7 dpc which are distinct from pluripotential cells in the early embryo because they can not colonize blastocysts. However, a portion of PGCs are transformed into pluripotential cells in the ectopic environment or in culture, suggesting that the developmental fate of PGCs may still be somewhat plastic. PGCs may be destined only for gametes after they enter into the mitotic arrest phase or the meiotic prophase in embryonic gonads, which may be regulated by intrinsic and/or environmental molecules. After fetal germ cells are mitotically arrested, a large number of germ cells undergo programmed cell death. Bcl-2 and its related molecules are involved in the determination of death or survival of fetal germ cells, as well as of spermatogonia in adult testis. The cell death of spermatogonia may be necessary either for eliminating impaired germ cells or for arranging optimal interactions between germ cells and their supporting cells. Although maturating germ cells seem to differentiate only to sperm cells, oocytes that complete the first meiotic division can give rise to pluripotential cells, suggesting that maternal molecules accumulated in oocyte may play a role in the restoration of pluripotency.

Animals↗

PubMed1991

Identifying and manipulating neuronal stem cells.

Fetal brain tissue has been shown to have clear behavioral effects when transplanted into adult lesioned brains. These results have focused attention on the cell types of the embryonic brain. Transplantation experiments using primary cells are beginning to define the plasticity of these cells and the times when they become committed to specific neuronal fates. Growth factors have been defined that regulate the proliferation of these cells in culture. Cell lines have been established that express stem cell properties and that are capable of differentiation when implanted into the developing brain. In this article we review this work on mammalian neuroepithelial stem cells and discuss how these studies might contribute to the therapeutic use of brain transplants.

Animals↗