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At least 73 records · Page 4Linked to original sources
PubMed2002

Growth of a virtual tumour using probabilistic methods of cell generation.

A study into treatment enhancement in combined chemo-radiotherapy for unresectable head and neck cancer has initiated the development of a computer model of tumour growth. The model is based on biological parameters, and characterises tumour growth prior to chemo-radiotherapy. Tumour growth starting from a single stem cell is modelled using the Monte Carlo method. The type of the cell function, their relative proportions on mitosis, their proliferative capacity, the duration of the four phases of the cell cycle, the mean cell cycle time, and the cell loss due to natural causes are the main parameters of the basic model. A Gaussian distribution function operates in establishing the cell cycle time, with a mean value of 33 hours, while the cell type is sampled from a uniform distribution. With the established model, the sensitivity of the developed tumour's cell population to the stem, proliferative and nonproliferative ratio at mitosis was assessed. The present model accurately reflects the exponential distribution of cells along the cell cycle (70% cells in GI phase, 15% in S, 10% in G2, 5% in M) of a developed tumour as described in the literature. The proportion of stem, finitely proliferating and resting cells during tumour growth is maintained within their biological limits (2% stem, 13% finitely proliferating, 85% nonproliferating cells). The ratio (R = 3) between the time necessary to develop a clinically detectable tumour (10(9) cells) and the further time to grow to its lethal size (10(12) cells) is in accordance with the biological data when tumour volume is compared for the two periods (30 doublings and 10 doublings respectively). In conclusion, computer simulation can illustrate the biological growth of a tumour and the cell distribution along the cell cycle. These distributions may then be used in the assessment of tumour response to radiotherapy and to specific chemotherapeutic agents.

Cell Count↗
PubMed2002

Mast cells derived from embryonic stem cells: a model system for studying the effects of genetic manipulations on mast cell development, phenotype, and function in vitro and in vivo.

Large quantities of highly enriched populations of mast cells can be generated from mouse embryonic stem (ES) cells using an in vitro differentiation system. These embryonic stem cell-derived mast cells (ESMCs) exhibit many similarities to mouse bone marrow-derived cultured mast cells (BMCMCs), including the abilities to survive and to orchestrate immunologically specific immunoglobulin E (IgE)-dependent reactions in vivo after transplantation into genetically mast cell-deficient KitW/KitW-v mice. Coupled with the current spectrum of techniques for genetically manipulating ES cells, ESMCs represent a unique model system to analyze the effects of specific alterations in gene structure, expression, or function, including embryonic lethal mutations, on mast cell development, phenotype, and function in vitro and in vivo.

Animals↗
PubMed2000

Autonomous behavior of hematopoietic stem cells.

Mechanisms that affect the function of primitive hematopoietic stem cells with long-term proliferative potential remain largely unknown. Here we assessed whether properties of stem cells are cell-extrinsically or cell-autonomously regulated. We developed a model in which two genetically and phenotypically distinct stem cell populations coexist in a single animal. Chimeric mice were produced by transplanting irradiated B6D2F1 (BDF1) recipients with mixtures of DBA/2 (D2) and C57BL/6 (B6) day-14 fetal liver cells. We determined the mobilization potential, proliferation, and frequency of D2 and B6 stem and progenitor cells in animals with chimeric hematopoiesis. After granulocyte colony-stimulating factor (G-CSF) administration, peripheral blood D2 colony-forming units granulocyte-macrophage were fourfold to eightfold more numerous than B6 progenitors. We determined that D2 and B6 progenitors maintained their genotype-specific cycling activity in BDF1 recipients. Chimeric marrow was harvested and D2 and B6 cell populations were separated by flow cytometry. Cobblestone area-forming cell (CAFC) analysis of sorted marrow showed that the number of late appearing CAFC subsets within the D2 cell population was approximately threefold higher than within the B6 fraction. We performed secondary transplantation using unfractionated chimeric marrow, which was given in limiting doses to lethally irradiated BDF1 recipients. Comparison of the proportion of animals possessing D2 and/or B6 leukocytes 5 months after transplant revealed that the frequency of D2 LTRA was approximately 10-fold higher than B6 LTRA numbers. Our data demonstrate that genetically distinct stem cell populations, coexisting in individual animals, independently maintain their parental phenotypes, indicating that stem cell properties are predominantly regulated cell-autonomously.

Animals↗
PubMed2000

Mesenchymal stem cells as vehicles for gene delivery.

Mesenchymal stem cells contribute to the regeneration of mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, adipose, and marrow stroma. Transduction of mesenchymal stem cells from species other than humans is required for the development of disease models in which mesenchymal stem cells-based gene delivery is evaluated. Attempts to transduce mesenchymal stem cells from some species with amphotropic retroviral vectors were unsuccessful, leading to comparative mesenchymal stem cells transductions with xenotropic and gibbon-ape leukemia virus envelope-pseudotyped retroviral vectors. Human, baboon, canine, and rat mesenchymal stem cells were transduced optimally with amphotropic vector supernatants. In contrast, sheep, goat, and pig mesenchymal stem cells showed highest transduction levels with xenotropic retroviral vector supernatant, and rabbit mesenchymal stem cells were transduced optimally with gibbon-ape-enveloped vectors. Using a myeloablative canine transplantation model and gene-marked canine mesenchymal stem cells, the biodistribution of infused and ex vivo expanded mesenchymal stem cells were examined. The majority of transduced canine mesenchymal stem cells were found in the bone marrow samples. The current study shows the use of mesenchymal stem cells as a delivery vehicle for gene transfer studies, and validates the feasibility of delivering mesenchymal stem cells to the marrow compartment for stromal regeneration after cancer-associated cytotoxic therapies.

Animals↗
PubMed2002

Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model.

Although implantation of fetal dopamine (DA) neurons can reduce parkinsonism in patients, current methods are rudimentary, and a reliable donor cell source is lacking. We show that transplanting low doses of undifferentiated mouse embryonic stem (ES) cells into the rat striatum results in a proliferation of ES cells into fully differentiated DA neurons. ES cell-derived DA neurons caused gradual and sustained behavioral restoration of DA-mediated motor asymmetry. Behavioral recovery paralleled in vivo positron emission tomography and functional magnetic resonance imaging data demonstrating DA-mediated hemodynamic changes in the striatum and associated brain circuitry. These results demonstrate that transplanted ES cells can develop spontaneously into DA neurons. Such DA neurons can restore cerebral function and behavior in an animal model of Parkinson's disease.

Adrenergic Agents↗
PubMed2025

Glycolytic activity instructs germ layer proportions through regulation of Nodal and Wnt signaling.

Metabolic pathways can influence cell fate decisions, yet their regulative role during embryonic development remains poorly understood. Here, we demonstrate an instructive role of glycolytic activity in regulating signaling pathways involved in mesoderm and endoderm specification. Using a mouse embryonic stem cell (mESC)-based in vitro model for gastrulation, we found that glycolysis inhibition increases ectodermal cell fates at the expense of mesodermal and endodermal lineages. We demonstrate that this relationship is dose dependent, enabling metabolic control of germ layer proportions through exogenous glucose levels. We further show that glycolysis acts as an upstream regulator of Nodal and Wnt signaling and that its influence on cell fate specification can be decoupled from its effects on growth. Finally, we confirm the generality of our findings using a human gastrulation model. Our work underscores the dependence of signaling pathways on metabolic conditions and provides mechanistic insight into the nutritional regulation of cell fate decision-making.

Glycolysis↗
PubMed2025

Dual-patterned pluripotent stem cells self-organize into a human embryo model with extended anterior-posterior patterning.

Human gastruloids are a powerful class of stem cell-derived models that recapitulate key features of early embryonic development, including symmetry breaking and the emergence of three germ layers1-3. However, they lack anterior embryonic structures and coordinated axial organization4-6. To address this limitation, we pre-patterned human pluripotent stem cells (hPSCs) by exposing them to either anterior (FGF2) or posterior (CHIR99021 [CHIR] & retinoic acid [RA]) cues. Upon mixing, these dual-patterned hPSCs interacted and self-organized into elongated structures with both anterior and posterior features-which we term anterior-posterior (AP) human gastruloids. Anteriorly pre-treated cells robustly intercalated into posteriorly pre-treated cells, collectively giving rise to a continuum of neural tissues-including a brain-like domain, a neural tube-like structure, and neuro-mesodermal progenitors (NMPs)-with segmented somites arrayed bilaterally. Single cell RNA sequencing (scRNA-seq) revealed that human AP gastruloids contain cell types resembling the midbrain-hindbrain boundary (MHB), regionalized hindbrain structures (i .e. rhombomeres 1-8), regionalized neural crest (i.e. cranial, vagal, trunk)7,8 and head mesoderm. Transcriptomic comparisons to primate embryos revealed that human AP gastruloids most closely resemble Carnegie stage 11 (CS11) embryos. While they lack a notochord and full dorsal-ventral polarity, human AP gastruloids recapitulate key spatial and temporal features of early neurulation and somitogenesis. Perturbation of folic acid metabolism or rho-associated kinase (ROCK) signaling induced spinal cord defects, phenocopying aspects of spina bifida and other neural tube defects, highlighting this model's potential for studying congenital disorders9. AP gastruloids may serve as a simple, robust, scalable platform for modeling coordinated human AP body axis development. More broadly, our results suggest that controlled interactions between differentially prepatterned progenitors can initiate self-organization of complex body axis features. The "pattern-and-mix" strategy may serve as a generalizable framework for assembling spatially organized stem cell models of mammalian development.

Journal Article↗
PubMed2005

Human embryonic stem cells: an in vitro model to study mechanisms controlling pluripotency in early mammalian development.

The property of pluripotency confers the capacity for differentiation into a large number of cell types including extra-embryonic, somatic and germinal cells. During normal development, pluripotency is acquired by the cells of the early embryo, which shortly thereafter undergo differentiation, whereas embryonic stem cells (ESCs) uniquely maintain pluripotency while undergoing extensive in vitro proliferation. Studies using ESCs have begun to unravel the network of cytokines and transcription factors responsible for their maintenance of pluripotency. Surprisingly, mouse and human ESCs display significant differences in such mechanisms despite their similar embryonic origins. In this review, we compare the properties of pluripotent embryonic cells with those of ESCs to establish a general model for the mechanisms maintaining pluripotency. We first consider whether mouse and human ESCs represent comparable stages of early embryonic development. We then describe how human embryoid body (EB) differentiation could be used as a model of embryonic development. Finally, to concretely illustrate the discussion, we discuss our recent results concerning Nodal function in controlling cell fate at early stages of human EB development. With the new perspective of these findings, we suggest a previously unrecognized role of TGF-beta pathway signaling in maintaining pluripotency at early stages of mammalian embryonic development.

Animals↗
PubMed2005

Transcriptional regulation of hematopoietic stem cell development in zebrafish.

The zebrafish (Danio rerio) is a well-established vertebrate model for studying hematopoiesis. The major advantages of this system include robust experimental techniques in both genetics and embryology, which have been utilized to model many aspects of human development and disease. Although much is known about the transcription factors involved in the terminal differentiation of peripheral blood lineages, little is known about the development and maintenance of the hematopoietic stem cell (HSC). This review will focus on the current knowledge of the transcriptional regulation of the HSC in the context of the zebrafish. Future studies using new technologies in the zebrafish model will enhance our understanding of the molecular networks regulating HSC pluripotency and differentiation.

Animals↗
PubMed2006

A novel experimental platform for investigating cancer growth and anti-cancer therapy in a human tissue microenvironment derived from human embryonic stem cells.

There is no available experimental system wherein human cancer cells can be grown in the context of a mixed population of normal differentiated human cells for testing biological aspects of cancer cell growth (tumor cell invasion, angiogenesis) or response to anti-cancer therapies. Human embryonic stem cells when implanted into immunocompromised mice develop teratomas containing complex structures, comprising differentiated cell types representing the major germline-derived lineages. We sought to determine whether human cancer cells would grow within such teratomas and display properties associated with malignancy such as invasiveness and recruitment of blood vessels. Ovarian cancer cells (HEY), stably expressing an H2A-GFP fusion protein, which allows tracking of tumor cells, were injected into mature teratomas and developed into tumors. The growth, proliferation capacity, invasion, and induction of blood vessel formation were examined. We propose using the novel experimental platform we have described, consisting of human tumor cells growing within a human cellular microenvironment derived from human embryonic stem cells, to develop a preclinical model for investigating and manipulating the stromal response in tumor cell growth, as an additional tool in cancer research.

Animals↗
PubMed1999

Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells.

The identification of molecules that regulate human hematopoietic stem cells has focused mainly on cytokines, of which very few are known to act directly on stem cells. Recent studies in lower organisms and the mouse have suggested that bone morphogenetic proteins (BMPs) may play a critical role in the specification of hematopoietic tissue from the mesodermal germ layer. Here we report that BMPs regulate the proliferation and differentiation of highly purified primitive human hematopoietic cells from adult and neonatal sources. Populations of rare CD34(+)CD38(-)Lin- stem cells were isolated from human hematopoietic tissue and were found to express the BMP type I receptors activin-like kinase (ALK)-3 and ALK-6, and their downstream transducers SMAD-1, -4, and -5. Treatment of isolated stem cell populations with soluble BMP-2, -4, and -7 induced dose-dependent changes in proliferation, clonogenicity, cell surface phenotype, and multilineage repopulation capacity after transplantation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Similar to transforming growth factor beta, treatment of purified cells with BMP-2 or -7 at high concentrations inhibited proliferation yet maintained the primitive CD34(+)CD38(-) phenotype and repopulation capacity. In contrast, low concentrations of BMP-4 induced proliferation and differentiation of CD34(+) CD38(-)Lin- cells, whereas at higher concentrations BMP-4 extended the length of time that repopulation capacity could be maintained in ex vivo culture, indicating a direct effect on stem cell survival. The discovery that BMPs are capable of regulating repopulating cells provides a new pathway for controlling human stem cell development and a powerful model system for studying the biological mechanism of BMP action using primary human cells.

Activin Receptors↗
PubMed1999

Extragonadal teratocarcinoma in chimeric mice.

Chimeric mice often are created through the genetic manipulation of the mouse embryo in the process of developing animal models of disease. These mice have variable percentages of their somatic and germ cells derived from the donor embryonic stem cells and host blastocysts. In the development of mouse models deficient in the breast cancer susceptibility gene 2 (Brca2) or the 70-kd heat shock protein (Hsp70-2), 3-4-week-old chimeras developed single or multiple masses composed of both well-differentiated and poorly differentiated tissues derived from all three germ layers. These cases of extragonadal teratocarcinoma, a rarely reported tumor, may be related to the genetic predisposition of the 129/Ola mouse strain used to generate the embryonic stem cells.

Animals↗
PubMed2002

Development of human lymphohematopoiesis defined by CD34 and CD81 expression.

Human blood cells, except for erythrocytes and platelets, express CD81, a member of the transmembrane 4 superfamily (TM4SF). CD81 is also expressed on most of human immature hematopoietic cells, CD34+ cells, which are divided into three populations according to the expression of CD34 and CD81; CD34+CD81+, CD34+CD81(High) and CD34(Low)CD81+. Myeloid and lymphoid progenitors exist in the CD34+CD81+ population, and megakaryocytic progenitors are only in CD34(Low)CD81+ population. Erythroid and multipotential progenitors are shared by CD34+CD81+ and CD34(Low)CD81+ populations, but multipotential progenitors in the CD34+CD81+ population have already lost most of their myeloid potential. NK cells and mast cells can be generated from all three populations. Long-term repopulating (LTR) lymphohematopoietic stem cells are present in the CD34+CD81+ population. Based on these findings, we propose a model for the development of CD34+CD81+ lymphohematopoietic stem cells. Along the differentiation cascade from CD34+CD81+ lymphohematopoietic stem cells, there appear to be pathways to CD34(Low)CD81 + or CD34+CD81(High) cells, even if they are indirect. CD34(Low)CD81+ pathways define the loss of LTR ability, and lymphoid and myeloid potentials, whereas CD34+CD81(High) pathways represent the exclusive commitment to NK cells and mast cells.

Animals↗
PubMed2005

Generation of embryoid bodies from mouse embryonic stem cells cultured on STO feeder cells.

Embryoid bodies, which are similar to post-implantation egg-cylinder stage embryos, provide a model for the study of embryo development and stem cell differentiation. We describe here a novel method for generating embryoid bodies from murine embryonic stem (ES) cells cultured on the STO feeder layer. The ES cells grew into compact aggregates in the first 3 days of coculture, then became simple embryoid bodies (EBs) possessing primitive endoderm on the outer layer. They finally turned into cystic embryoid bodies after being transferred to Petri dishes for 1-3 days. Evaluation of the EBs in terms of morphology and differentiating potential indicates that they were typical in structure and could generate cells derived from the three germ layers. The results show that embryoid bodies can form not only in suspension culture but also directly from ES cells cultured on the STO feeder layer.

Animals↗
PubMed1998

Differentiation of human pluripotent teratocarcinoma stem cells induced by bone morphogenetic protein-2.

Pluripotent human teratocarcinoma stem cells cultured in vitro provide a resource for the study of early embryonic development in man, as well as a means for discovery of novel factors controlling cell differentiation and commitment. We previously reported that the human teratocarcinoma stem cell line GCT 27X-1 could be induced to differentiate into an endodermal progenitor cell by treatment with high doses of retinoic acid. A search for polypeptide inducers of differentiation in this system has identified bone morphogenetic protein-2 (BMP-2) as a potent inducer of differentiation. In cell line GCT 27X-1, treatment with BMP-2 reduces proliferation, induces morphological changes similar to obtained following treatment with retinoic acid, and causes a decrease in the expression of transcripts for the stem cell markers CD30 and Oct-4. Preliminary immunochemical studies indicate that the differentiated cells produced by BMP-2 are endodermal precursors with a pattern of marker expression similar to that found in retinoic acid treated cells. Models of endoderm differentiation in humans will be useful for identifying the molecules which mediate cell interactions in development, and in achieving directed differentiation of cells for use in transplantation.

Animals↗
PubMed1992

A model of the control of cellular regeneration in the intestinal crypt after perturbation based solely on local stem cell regulation.

The control mechanisms involved in regeneration of murine intestinal crypts after perturbations are presently not well understood. The existence of some feedback signals from the cells on the villus to the cells in the crypt has been suggested. However, some recent experimental data point to the fact that regeneration in the crypt starts very early after perturbation, at a time when the villus cell population has hardly changed. In particular, this early cell proliferative activity is seen specifically at the bottom of the crypt, i.e. in the presumed stem cell zone and furthest from the villus. The objective of this study was to investigate whether a new concept of regulation operating solely at the stem cell level could explain the present mass of accumulated data on the post-irradiation recovery, which is an extensively studied perturbation from the experimental point of view. In order to check its validity, the new concept was formalized as a mathematical simulation model thus enabling comparison with experimental data. The model describes the cellular development from stem cells to the mature villus cells. As a basic feature it is assumed that the self-maintenance and the cell cycle activity of the stem cells are controlled by the number of these cells in an autoregulatory fashion. The essential features of the experimental data (i.e. the recovery with time and the consistency between different types of measurements) can be very well reproduced by simulations using a range of model parameters. Thus, we conclude that stem cell autoregulation is a valid concept which could replace the villus crypt feedback concept in explaining the early changes after irradiation when the damage primarily affects the crypt. The question of the detailed nature of the control process requires further investigation.

Animals↗
PubMed1995

Presence of nerve growth factor and its receptors in an in vitro model of islet cell development: implication in normal islet morphogenesis.

In vivo, the differentiation of pancreatic islet stem cells depends on unknown soluble factors produced by the mesenchyme surrounding these cells. We have previously demonstrated that, like some neuronal cells, different beta-cell lines express functional nerve growth factor (NGF) receptors and can respond to NGF by extending neurite-like processes. NGF receptors are also expressed in vivo in mature rat islets and early during development in pancreatic ductular cells, which represent putative beta-stem cells. In this study, we have further characterized an in vitro model of islet development and studied the expression of NGF receptors and its ligand in this model. We have demonstrated the expression of Trk-A messenger RNA coding for the high affinity NGF receptor in islet cells and the localization of Trk protein in both alpha- and beta-islet cells. Moreover, the cells, from which islet cells "bud," also express Trk-A. Furthermore, NGF is produced and secreted by the nonendocrine cells surrounding the islets, suggesting a possible paracrine mode of action of NGF on the adjacent islet cells. Finally, islet morphogenesis is significantly retarded in the presence of K252a, an inhibitor of the tyrosine kinase activity of the family of Trk receptors, suggesting an implication of the neurotrophin-neurotrophin receptor axis in islet development.

Animals↗