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Results for “cell fate plasticity”

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PubMed2006

Neural crest cell plasticity. size matters.

Patterning and morphogenesis of neural crest-derived tissues within a developing vertebrate embryo rely on a complex balance between signals acquired by neural crest cells in the neuroepithelium during their formation and signals from the tissues that the neural crest cells contact during their migration. Axial identity of hindbrain neural crest is controlled by a combinatorial pattern of Hox gene expression. Cellular interactions that pattern neural crest involve signals from the same key molecular families that regulate other aspects of patterning and morphogenesis within a developing embryo, namely the BMP, SHH and FGF pathways. The developmental program that regulates neural crest cell fate is both plastic and fixed. As a cohort of interacting cells, neural crest cells carry information that directs the axial pattern and species-specific morphology of the head and face. As individual cells, neural crest cells are responsive to signals from each other as well as from non-neural crest tissues in the environment. General rules and fundamental mechanisms have been important for the conservation of basic patterning of neural crest, but exceptions are notable and relevant. The key to furthering our understanding of important processes such as craniofacial development will require a better characterization of the molecular determinants of the endoderm, ectoderm and mesoderm and the effects that these molecules have on neural crest cell development.

Animals↗

PubMed2001

Plasticity in zebrafish hox expression in the hindbrain and cranial neural crest.

The anterior-posterior identities of cells in the hindbrain and cranial neural crest are thought to be determined by their Hox gene expression status, but how and when cells become committed to these identities remain unclear. Here we address this in zebrafish by cell transplantation, to test plasticity in hox expression in single cells. We transplanted cells alone, or in small groups, between hindbrain rhombomeres or between the neural crest primordia of pharyngeal arches. We found that transplanted cells regulated hox expression according to their new environments. The degree of plasticity, however, depended on both the timing and the size of the transplant. At later stages transplanted cells were more likely to be irreversibly committed and maintain their hox expression, demonstrating a progressive loss of responsiveness to the environmental signals that specify segmental identities. Individual transplanted cells also showed greater plasticity than those lying within the center of larger groups, suggesting that a community effect normally maintains hox expression within segments. We also raised experimental embryos to larval stages to analyze transplanted cells after differentiation and found that neural crest cells contributed to pharyngeal cartilages appropriate to the anterior-posterior level of the new cellular environment. Thus, consistent with models implicating hox expression in control of segmental identity, plasticity in hox expression correlates with plasticity in final cell fate.

Animals↗

PubMed2005

Protein kinase signaling cascades in CNS trauma.

Advances in our understanding of the signaling pathways and cellular functions regulated by protein kinase cascades have paved the way to study their role in the response of brain and spinal cord to traumatic injury. Mechanical forces imparted by trauma stimulate mitogen-activated protein kinases and protein kinase B/Akt as well as cause changes in the state of phosphorylation of glycogen synthase kinase-3beta. Extracellular ATP released by mechanical strain stimulates P2 purinergic receptors that are coupled to these protein kinase signaling pathways. These kinases regulate gene expression, cell survival, proliferation, differentiation, growth arrest, and apoptosis, thereby affecting cell fate, repair and plasticity after trauma. Elucidation of the molecular responses of protein kinase cascades to mechanical strain and the genes regulated by these signaling pathways may lead to therapeutic opportunities to minimize losses in motor skills and cognitive function caused by trauma to the central nervous system.

Animals↗

PubMed2003

Efficient characterization of retro-, lenti-, and foamyvector-transduced cell populations by high-accuracy insertion site sequencing.

The identification of unknown genomic flanking DNA sequences can be used for the molecular monitoring of retro-, lenti- and foamyviral integration, transgenes in early embryogenesis, insertional mutagenesis, cell fate, and stem cell plasticity. Most existing methods reflect shortcomings in sensitivity and or specificity, thus limiting genomic sequencing of unknown flanking DNA to clonal preparations. The application of linear amplification-mediated PCR (LAM-PCR), a recently developed direct sequencing technique for flanking DNA, should circumvent current limitations in different research fields. This technique combines preamplification of target DNA with a unique succession of enzymatic reactions on solid-phase. Using LAM-PCR, we show the previously unfeasible in vivo retro-, lenti- and foamyvirus integration site analysis in primate peripheral blood hematopoietic cells and human xenograft hematopoiesis. In light of two severe adverse events that occurred in a clinical SCID-X1 gene therapy trial, in vivo monitoring of the reinfused transduced cell pool by integration site analysis will be an important component of each gene transfer and therapy study aimed at clinical use.

Animals↗

PubMed2001

Cell fate specification in the cereal endosperm.

While superficially simple, endosperm development is a complex, dynamic process. Cereal endosperms contain three major cell types: starchy endosperm, transfer cells and aleurone. The localized accumulation of the END1 transcript in the syncitial endosperm suggests that signals from the maternal placental tissue specify transfer cell type early. Aleurone fate is plastic and requires the continual input of positional cues to maintain cell identity. Starchy endosperm appears to be the default cell type. Mutant patterns suggest that a regulatory hierarchy integrates endosperm development. Requirements for gametic imprinting, maternal : paternal genome ratios and putative chromatin modeling factors indicate the importance of genomic control.

Cell Differentiation↗

PubMed1988

Fusion of liposomes with the plasma membrane of epithelial cells: fate of incorporated lipids as followed by freeze fracture and autoradiography of plastic sections.

The fusion of liposomes with the plasma membrane of influenza virus-infected monolayers of an epithelial cell line, Madin-Darby canine kidney cells (van Meer et al., 1985. Biochemistry. 24:3593-3602), has been analyzed by morphological techniques. The distribution of liposomal lipids over the apical and basolateral plasma membrane domains after fusion was assessed by autoradiography of liposomal [3H]dipalmitoylphosphatidylcholine after rapid freezing or chemical fixation and further processing by freeze substitution and low temperature embedding. Before fusion, radioactivity was solely detected on the apical cell surface, indicating the absence of redistribution artifacts and demonstrating the reliability of lipid autoradiography on both a light and electron microscopical level. After induction of fusion by a low pH treatment, the basolateral plasma membrane domain became progressively labeled, indicative of rapid lateral diffusion of [3H]dipalmitoylphosphatidylcholine in the plasma membrane. Analysis of individual fusion events by freeze fracture after rapid freezing confirmed the rapid diffusion of the liposomal lipids into the plasma membrane, as intramembrane particle-free lipid patches were never observed. After the induction of liposome-cell fusion, well-defined intramembrane particles were present on the otherwise smooth liposomal fracture faces and on the fracture faces of the plasma membrane. Morphological evidence thus was obtained in favor of a local point fusion mechanism with an intramembrane particle as a specific structural fusion intermediate.

Animals↗

PubMed2002

Evidence that fibroblasts derive from epithelium during tissue fibrosis.

Interstitial fibroblasts are principal effector cells of organ fibrosis in kidneys, lungs, and liver. While some view fibroblasts in adult tissues as nothing more than primitive mesenchymal cells surviving embryologic development, they differ from mesenchymal cells in their unique expression of fibroblast-specific protein-1 (FSP1). This difference raises questions about their origin. Using bone marrow chimeras and transgenic reporter mice, we show here that interstitial kidney fibroblasts derive from two sources. A small number of FSP1(+), CD34(-) fibroblasts migrate to normal interstitial spaces from bone marrow. More surprisingly, however, FSP1(+) fibroblasts also arise in large numbers by local epithelial-mesenchymal transition (EMT) during renal fibrogenesis. Both populations of fibroblasts express collagen type I and expand by cell division during tissue fibrosis. Our findings suggest that a substantial number of organ fibroblasts appear through a novel reversal in the direction of epithelial cell fate. As a general mechanism, this change in fate highlights the potential plasticity of differentiated cells in adult tissues under pathologic conditions.

Animals↗

PubMed2000

Three to four-year-old nonpassaged EGF-responsive neural progenitor cells: proliferation, apoptosis, and DNA repair.

Epidermal growth factor responsive (EGFr) neural progenitor (NP) cells have been shown to be a potential alternative tissue source for neural transplantation and for developmental study. We have shown that nonpassaged EGFr NP cells can self-renew for 2 years in neurospheres and can robustly differentiate into glia and a number of neuronal cell types. We are now attempting to investigate if the EGFr NP cells will die or continue to live beyond the life span of the donor. In addition, we and other investigators have also found that EGFr NP cells, after transplant, retain only a small number of cells in the transplant site. In this study, we investigate the plasticity and fate of the EGFr NP cells. Using the nonpassaged method, we found EGFr NP cells live in the EGF supplement medium for over 4 years-the longest-lived EGFr NP cells ever reported. The 4-year-old striatal or cortical EGFr neurospheres, when subplated with substrate coating, migrate out of neurospheres and have robust growth with many processes. Furthermore, when nucleotide marker bromodeoxyuridine (BrdU) was added 3 days prior to the subplating, the EGFr NP cells were labeled positively with BrdU in the nucleus, indicating active proliferation activity. Meanwhile two other events were also found in the long-term EGFr NP cells. In the midst of the proliferation, apoptosis occurred. A subpopulation of EGFr NP cells are undergoing programmed cell death as indicated by the cell morphology and the TUNEL staining for DNA strand breaks. The TUNEL fluorescein-staining indicates that over 50% of EGFr NP cells are positive in the nuclei. On the other hand, we have also found that the major base excision repair enzyme, APE/ref-1, which is responsible for recognizing and repairing baseless sites in DNA, was present in the progenitor cells. However, in those cells undergoing apoptosis, APE/ref-1 levels were dramatically reduced or missing, and only a small percentage of cells were TUNEL and APE/ref-1 positive. These observations indicate that EGFr neural progenitor cells can live beyond the life span of the donor animal. The longevity of these cells in culture may be enhanced due to decreased apoptosis and the retention of normal DNA repair capacity.

Animals↗

PubMed2025

Genome-wide association meta-regression identifies stem cell lineage orchestration as a key driver of acne risk.

Over 85% of the population experience acne at some point in their lives, with its severity spanning a quantitative spectrum, from mild, transient outbreaks to more persistent, severe forms of the condition. Moderate to severe disease poses a substantial global burden arising from both the physical and psychological impacts of this highly visible condition. The analytical approach taken in this study aimed to address the impact of variation in the dichotomisation of acne case control status, driven by ascertainment and study design, on effect size estimates across independent genetic association studies of acne. Through a fixed intercept meta-regression framework, we combined evidence genome-wide for association with acne across studies in which case-control status had been ascertained in different settings, allowing for different severity threshold definitions. Across a combined sample of 73,997 cases and 1,103,940 controls of European, South Asian and African American ancestry we identify genetic variation at 165 genomic loci that influence acne risk. There is evidence for both shared and ancestry specific components to the genetic susceptibility to acne and for sex differences in the magnitude of effect of risk alleles at three loci. We observe that common genetic variation explains 13.4% of acne heritability on the liability scale. Consistent with the hypothesis that genetic risk primarily operates at the level of individual pilosebaceous units, a polygenic score derived from this case-control study of acne susceptibility is associated with both self-reported and clinically assessed acne severity in adolescence, further strengthening the link between genetic risk and disease severity. Prioritisation of causal genes at the identified acne risk loci, provides genetic validation of the targets of established and emerging acne therapies, including retinoid treatments. The identified acne risk loci are enriched for genes encoding downstream effectors of RXRA signalling, including SOX9 and components of the WNT and p53 pathways. Illustrating that the control of stem cell lineage plasticity and cellular fate are important mechanisms through which genetic variation influences acne susceptibility within the pilosebaceous unit.

Journal Article↗

PubMed2002

Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry.

BACKGROUND: Tumor cell plasticity represents a significant clinical challenge in that the fate and function of tumor cells can be elusive until a tumor mass is evident. A remarkable example of plasticity is tumor cell vasculogenic mimicry, recently described in aggressive uveal and cutaneous melanoma, in addition to ovarian carcinoma, whereby tumor cells express endothelial-associated genes and form de novo vasculogenic-like networks in three-dimensional (3-D) culture. In the current investigation, we examined whether there is evidence for vasculogenic mimicry in heterogeneous prostatic neoplasms. METHODS: Dunning rat and human prostate cancer cell lines (comprised of epithelial- and fibroblastic-like tumor subpopulations) were tested for their ability to express selected endothelial-associated genes, laminin, the alpha6beta1 laminin-binding integrin, and for their potential to form perfusable tubular networks in 3-D culture. Simultaneous morphological analysis of tumor-lined channels in rat and human tumors was also performed. RESULTS: Green fluorescent protein labeling of prostatic clonal subpopulations revealed unique cooperative interactions of epithelial- and fibroblastic-like tumor cells in the formation of perfusable vasculogenic-like networks. Furthermore, while these cell lines were shown to express various vascular markers, prostatic tumor cell-lined channels were also detected in vivo in high grade tumors, and occurred in some cases in close proximity to conventional endothelial-lined vasculature. CONCLUSIONS: A multidisciplinary approach to assess vasculogenic mimicry by prostatic tumor cells has revealed supportive evidence that it occurs in invasive, heterogeneous prostate cancer cell lines, and circumstantially in aggressive rat and human tumors. These results reflect the plasticity of aggressive prostatic tumor cells and may provide new prognostic markers for clinical diagnosis and new therapeutic intervention strategies.

Animals↗

PubMed2005

Adult bone marrow stem/progenitor cells (MSCs) are preconditioned by microenvironmental "niches" in culture: a two-stage hypothesis for regulation of MSC fate.

Mesenchymal stem cells (MSCs) are clonal, plastic adherent cells from bone marrow that can differentiate into various tissue lineages, including osteoblasts, adipocytes, chondrocytes, myoblasts, hepatocytes, and possibly even neural cells. Because MSCs are multipotent and their numbers are easily expanded in culture, there has been much interest in their clinical potential for tissue repair and gene therapy. Consequently, numerous studies have been carried out demonstrating the migration and multiorgan engraftment potential of MSCs in animal models and in human clinical trials. Understanding the mechanisms behind MSC cell fate determination is not easy, because the molecular processes that drive engraftment and differentiation are complex. Even in an in vitro system, the molecular cues necessary to induce differentiation are not easily identified or reproduced. In this Perspective, we emphasize the importance of microenvironmental factors in culture and suggest that MSC differentiation in vitro is regulated by a two-stage mechanism involving preconditioning by factors in the culture microenvironment followed by response to soluble differentiating factors.

Adult↗

PubMed2004

Characterization of tissue specific expression of Notch-1 in human tissues.

Signaling through the Notch cell surface receptors is a highly conserved mechanism of cell fate specification. Notch signaling regulates proliferation, differentiation and cell death. In vertebrates, putative gene duplication has originated four Notch genes, Notch-1, -2, -3 and -4. They have been implicated in neurogenesis, hematopoiesis, T-cell development, vasculogenesis and brain cortical growth. We have investigated Notch-1 distribution in normal human tissues by immunohistochemistry and immunoblot. We detected widespread expression of Notch-1 cytoplasmatic staining, with different tissue distributions in the different organs examined. In particular, high expression of Notch-1 was detected in the intermediate suprabasal layers, but not in the dead cells at the extreme periphery of stratified epithelia. Moreover, a low/intermediate level of Notch-1 was observed in lymphocytes in several peripheral lymphoid tissues; in particular the germinal centers of lymph nodes showed the most abundant number of positive cells, which appeared to be centroblasts/immunoblasts based on nuclear morphology. Notch-1 participates in keratinocytes differentiation. We showed by Western blot analysis that Notch-1 level was clearly increased in HaCaT cells after Ca(++) addition and remained substantially elevated until late differentiation stages. These results suggest that Notch-1 may function in numerous cell types in processes beyond cell fate determination, such as neuronal plasticity, muscle hypertrophy, liver regeneration, and germinal center lymphopoiesis during the immune response.

Blotting, Western↗

PubMed2006

Notch signaling reveals developmental plasticity of Pax4(+) pancreatic endocrine progenitors and shunts them to a duct fate.

Relatively little is known about the developmental signals that specify the types and numbers of pancreatic cells. Previous studies suggested that Notch signaling in the pancreas inhibits differentiation and promotes the maintenance of progenitor cells, but it remains unclear whether Notch also controls cell fate choices as it does in other tissues. To study the impact of Notch in progenitors of the beta cell lineage, we generated mice that express Cre-recombinase under control of the Pax4 promoter. Lineage analysis of Pax4(+) cells demonstrates they are specified endocrine progenitors that contribute equally to four islet cell fates, contrary to expectations raised by the dispensable role of Pax4 in the specification of the alpha and PP subtypes. In addition, we show that activation of Notch in Pax4(+) progenitors inhibits their differentiation into alpha and beta endocrine cells and shunts them instead toward a duct fate. These observations reveal an unappreciated degree of developmental plasticity among early endocrine progenitors and raise the possibility that a bipotent duct-endocrine progenitor exists during development. Furthermore, the redirection of Pax4(+) cells from alpha and beta endocrine fates toward a duct cell type suggests a positive role for Notch signaling in duct specification and is consistent with the more widely defined role for Notch in cell fate determination.

Journal Article↗

PubMed2002

[Plasticity of stem cells: a change of paradigm?].

Until a few years ago, an interest in stem cells, mostly of hematopoietic origin, was limited to a relatively small representation of scientists and clinicians seeking to understand the role of these rare cells in tissue homeostasis and to utilize their remarkable potential to regenerate an adult tissue following transplantation. Over the last few years, an ability of bone marrow-, brain-, muscle- and other tissue-derived stem cells to branch off, move between tissues and contribute to their repair was discovered. According to this novel view, at least a subset of stem cells may alter their fate in a manner that is more plastic and dynamic than previously thought, causing a fascination with these cells to spread to nearly all clinical disciplines. Expectations are high: stem cells are considered a future remedy for major diseases of our civilization. There are more questions raised than answers, and pressure grows to extend the knowledge and accelerate its implementation.

Adult↗

PubMed2000

A model of retinal cell differentiation in the chick embryo.

This article presents an overview of retinal cell differentiation in the chick embryo, in the context of a hypothetical model based on information generated during the last several years. The model proposes that: (1) most (if not all) proliferating neuroepithelial cells have the potential to give rise to a progeny comprising two or more different cell types; (2) the time at which cells undergo their terminal mitosis does not determine their differentiated fate; (3) many postmitotic precursor cells remain plastic (i.e., uncommitted) for some time after terminal mitosis, during which they encounter position-dependent signals as they migrate toward their definitive laminar position within the retina; (4) as a consequence of these inductive stimuli, precursor cells that migrate to different retinal layers express different transcriptional regulators; (5) morphologically undifferentiated precursor cells are committed to cell type-specific, complex patterns of differentiation, which they can express even when isolated from their normal microenvironment, and (6) even after precursor cells become committed to a specific identity, additional inductive signals are necessary for the cells to complete the development of a fully mature phenotype. The article presents a summary of the supportive evidence, as well as a critical evaluation of the model, and concludes with an overview of unanswered questions regarding retinal cell differentiation and a brief evaluation of the prospects for further progress in this field.

Animals↗

PubMed1994

Cranial paraxial mesoderm: regionalisation of cell fate and impact on craniofacial development in mouse embryos.

A combination of micromanipulative cell grafting and fluorescent cell labelling techniques were used to examine the developmental fate of the cranial paraxial mesoderm of the 8.5-day early-somite-stage mouse embryo. Mesodermal cells isolated from seven regions of the cranial mesoderm, identified on the basis of their topographical association with specific brain segments were assessed for their contribution to craniofacial morphogenesis during 48 hours of in vitro development. The results demonstrate extensive cell mixing between adjacent but not alternate groups of mesodermal cells and a strict cranial-to-caudal distribution of the paraxial mesoderm to craniofacial structures. A two-segment periodicity similar to the origins of the branchial motor neurons and the distribution of the rhombencephalic neural crest cells was observed as the paraxial mesoderm migrates during formation of the first three branchial arches. The paraxial mesoderm colonises the mesenchymal core of the branchial arches, consistent with the location of the muscle plates. A dorsoventral regionalisation of cell fate similar to that of the somitic mesoderm is also found. This suggests evolution has conserved the fate of the murine cranial paraxial mesoderm as a multiprogenitor population which displays a predominantly myogenic fate. Heterotopic transplantation of cells to different regions of the cranial mesoderm revealed no discernible restriction in cell potency in the craniocaudal axis, reflecting considerable plasticity in the developmental fate of the cranial mesoderm at least at the time of experimentation. The distribution of the different groups of cranial mesoderm matches closely with that of the cranial neural crest cells suggesting the two cell populations may share a common segmental origin and similar destination.

Animals↗

PubMed2003

Tendon morphogenesis in the developing avian limb: plasticity of fetal tendon fibroblasts.

The differentiation and patterning of tendon fibroblasts is at present a poorly understood aspect of musculoskeletal development in the vertebrate limb. Precursors of tendon fibroblasts originate in the somatic mesoderm adjacent to the early limb bud and gradually become incorporated into the limb mesenchyme as development proceeds. It is unclear whether these progenitor cells are committed to the tendon lineage at this early stage, or whether cells become committed only as they are incorporated into a developing tendon. Following a review of our current knowledge of early tendon development, we present recent results from our preliminary studies looking at tendon cell commitment. Using a lacZ encoding replication-deficient retrovirus, we have mapped regions of the early limb bud that contain presumptive tendon progenitor cells, and later used these sites for implanting labelled fetal tendon fibroblasts into developing limbs. Following implantation, we found that these cells successfully re-incorporated into developing proximal and distal tendons, but also surprisingly contributed to other tissue lineages within the limb. Our results suggest that fetal tendon fibroblasts may not be irreversibly committed to a tendon cell fate in the limb and may be somewhat plastic in their ability to integrate into other tissue lineages during development.

Animals↗

PubMed2006

Neural differentiation of human mesenchymal stem cells: Evidence for expression of neural markers and eag K+ channel types.

OBJECTIVE: Mesenchymal stem cells (MSCs) are multipotent cells that can self-renew, proliferate, and exhibit elevated cellular plasticity. To investigate their possible neural fate, we studied human mesenchymal stem cells (hMSCs) in different cell culture conditions from morphological, immunochemical, gene expression, and physiological points of view. MATERIALS AND METHODS: We tested hMSCs in three previously reported experimental conditions made of alpha-modified minimum essential medium (alpha-MEM)/1 mM beta-mercaptoethanol (betaME), 10 microM alpha-MEM/retinoic acid (RA) or alpha-MEM/2% dimethylsulfoxide (DMSO) + 200 microM beta-hydroxyanisole (BHA), respectively, and in a new experimental condition with neural progenitor maintenance medium (NPMM). RESULTS: hMSCs were isolated from bone marrow and expanded for several passages. In betaME, cells became immunoreactive for neuronal nuclear antigen (NeuN), neuron-specific enolase (NSE), Nestin, and glial fibrillary acidic protein (GFAP). In experimental conditions with RA and DMSO/BHA, hMSCs were NeuN and NSE-positive while in NPMM they were positive for GFAP and NSE. Untreated hMSCs showed a weak mRNA expression for microtubule-associated protein, NSE, and neurofilament protein-medium and GFAP, which strongly increased in NPMM-treated hMSCs. In the electrophysiological study, NPMM-differentiated hMSCs expressed two delayed rectifier K+ currents related to two ether-à-go-go K+ channels (eag1, eag2), which are fundamental for setting the negative resting potentials required for neuronal survival and basal cell activity. The two K+ channels were absent in undifferentiated hMSCs. These data were confirmed by real-time polymerase chain reaction. CONCLUSION: In our new culture condition, hMSCs acquired new morphological characteristics, neural markers, and electrophysiological properties, which are suggestive of neural differentiation. This might lead to clinical use of hMSCs in neural degenerative diseases.

Cell Culture Techniques↗