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PubMed2005

A germ cell origin of embryonic stem cells?

Because embryonic stem (ES) cells are generally derived by the culture of inner cell mass (ICM) cells, they are often assumed to be the equivalent of ICM cells. However, various evidence indicates that ICM cells transition to a different cell type during ES-cell derivation. Historically, ES cells have been believed to most closely resemble pluripotent primitive ectoderm cells derived directly from the ICM. However, differences between ES cells and primitive ectoderm cells have caused developmental biologists to question whether ES cells really have an in vivo equivalent, or whether their properties merely reflect their tissue culture environment. Here, we review recent evidence that the closest in vivo equivalent of an ES cell is an early germ cell.

Animals↗

PubMed1994

Cloning and characterization of the mouse XPAC gene.

Xeroderma Pigmentosum is a human disease, which is, among others, characterized by a high incidence of (sunlight induced) skin cancer, due to a defect in nucleotide excision repair (NER). The human DNA repair gene XPAC corrects this defect in cells isolated from Xeroderma Pigmentosum complementation group A (XP-A) patients. To enable the development of a transgenic mouse model for XP-A by gene targeting in embryonic stem cells, we cloned and characterized the mouse homologue of the XPAC gene. The mouse XPAC gene was found to consist of 6 exons, spanning approximately 21 kb. The nucleotide sequence of the exons is identical to that of the also cloned the mouse XPAC cDNA. Furthermore, the deduced amino acid sequence of the XPAC protein is the same as the one published previously by Tanaka et al. From CAT assay analysis, the promoter of the XPAC gene appeared to be located within 313 bp upstream of the assumed transcriptional start site. Like the promoters of other eukaryotic DNA repair genes (i.e. ERCC-1 and XPBC/ERCC-3), the mouse XPAC promoter region lacks classical promoter elements like TATA-, GC- and CAAT boxes. However, it contains an unique polypyrimidine-rich box, which is so far only found in genes encoding DNA repair enzymes. The function of this box in the regulation of transcription is still unclear.

Animals↗

PubMed2004

Molecular hierarchy in neurons differentiated from mouse ES cells containing a single human chromosome 21.

Defects in neurogenesis and neuronal differentiation in the fetal brain of Down syndrome (DS) patients lead to the apparent neuropathological abnormalities and contribute to the phenotypic characters of mental retardation, and premature development of Alzheimer's disease, those being the most common phenotype in DS. In order to understand the molecular mechanism underlying the cause of phenotypic abnormalities in the DS brain, we have utilized an in vitro model of TT2F mouse embryonic stem cells containing a single human chromosome 21 (hChr21) to study neuron development and neuronal differentiation by microarray containing 15K developmentally expressed cDNAs. Defective neuronal differentiation in the presence of extra hChr21 manifested primarily the post-transcriptional and translational modification, such as Mrpl10, SNAPC3, Srprb, SF3a60 in the early neuronal stem cell stage, and Mrps18a, Eef1g, and Ubce8 in the late differentiated stage. Hierarchical clustering patterned specific expression of hChr21 gene dosage effects on neuron outgrowth, migration, and differentiation, such as Syngr2, Dncic2, Eif3sf, and Peg3.

Alzheimer Disease↗

PubMed2005

Dynamics of chronic myeloid leukaemia.

The clinical success of the ABL tyrosine kinase inhibitor imatinib in chronic myeloid leukaemia (CML) serves as a model for molecularly targeted therapy of cancer, but at least two critical questions remain. Can imatinib eradicate leukaemic stem cells? What are the dynamics of relapse due to imatinib resistance, which is caused by mutations in the ABL kinase domain? The precise understanding of how imatinib exerts its therapeutic effect in CML and the ability to measure disease burden by quantitative polymerase chain reaction provide an opportunity to develop a mathematical approach. We find that a four-compartment model, based on the known biology of haematopoietic differentiation, can explain the kinetics of the molecular response to imatinib in a 169-patient data set. Successful therapy leads to a biphasic exponential decline of leukaemic cells. The first slope of 0.05 per day represents the turnover rate of differentiated leukaemic cells, while the second slope of 0.008 per day represents the turnover rate of leukaemic progenitors. The model suggests that imatinib is a potent inhibitor of the production of differentiated leukaemic cells, but does not deplete leukaemic stem cells. We calculate the probability of developing imatinib resistance mutations and estimate the time until detection of resistance. Our model provides the first quantitative insights into the in vivo kinetics of a human cancer.

Benzamides↗

PubMed2005

Stem cell therapy for cardiac arrhythmias.

Clinical studies suggest that stem cell transplantation (SCT) is feasible and has the potential for beneficial effects in several cardiac affections, including myocardial infarction and advanced heart failure. However, concern exists about the possible occurrence of serious arrhythmias after SCT, even if such complication has been shown only in case of skeletal myoblast transplantation. SCT might induce arrhythmias by several mechanisms, such as electrotonic stimulation of cardiac cells, electrical heterogeneity of action potentials during stem cell differentiation process, increased nerve sprouting, and local tissue injury induced by intramyocardial injection. As a matter of fact, the use of endothelial progenitor cells from the peripheral blood or of stem cells from bone marrow has not been associated with any significant cardiac rhythm disturbance. Recently, a new opportunity for SCT has emerged: the development of a biological cardiac pacemaker. Both gene therapy and cell therapy have been used in this new perspective. In fact, at present, the transformation of a normal cardiomyocyte in a pacemaker cell can be obtained in animal models by the injection of a plasmid or virus, incorporating the gene encoding for specific proteins. This procedure transforms cardiomyocytes in transgenic cells that may show an overexpression of beta2-adrenergic receptors, or abnormal membrane ion channels. As an alternative, genetically modified mesenchymal stem cells can be delivered within the heart and engraft to develop a biological pacemaker. To date, several studies have been performed in different animal models employing both cell and gene therapy. However, complex problems concerning safety and efficacy require a solution before we can move to the step of clinical evaluation in human beings.

Arrhythmias, Cardiac↗

PubMed2026

A human-specific non-coding RNA for EFHC1, an epilepsy-associated gene, regulates neural stem cell proliferation for cortical development.

Epilepsy is a prevalent brain disorder in humans but rarely occurs naturally in other species, highlighting the potential for human-specific mechanisms in its pathogenesis, and thus, current animal models fail to recapitulate human symptoms. Comparing RNA sequencing (RNA-seq) datasets from human and mouse neural stem cells (NSCs), we identified EFHC1, a juvenile myoclonic epilepsy gene, as exhibiting a human-biased expression. EFHC1 knockdown reduced human NSC proliferation, while its overexpression in mouse embryonic brains increased cortical NSC number. Mechanistically, EFHC1 prevented endoplasmic reticulum stress, thereby reducing inflammatory activation of p38 MAPK and promoting continuous proliferation of human NSCs. We also identified pancEFHC1, a bidirectional promoter-associated non-coding RNA (pancRNA), located at the human EFHC1 promoter. Knockdown of pancEFHC1 in human NSCs increased DNA methylation to reduce EFHC1 expression, with the resulting phenotype rescued by EFHC1 overexpression. We propose that the evolutionary acquisition of pancEFHC1 has introduced a complex regulatory mechanism for EFHC1 expression that allows distinguishing it in humans.

Humans↗

PubMed1997

New rodent models for studies of chemopreventive agents.

Some recent studies of the effects of chemopreventive agents have begun to use new rodent models to improve the analysis of stages of colonic preneoplasia, and how chemopreventive agents modify progressive abnormal cell development. In one of the models of inherited predisposition to colon cancer, mice carrying a truncated Apc allele with a nonsense mutation in exon 15 have been generated by gene targeting and embryonic stem cell technology (Apc1638 mice). These mice develop multiple gastrointestinal lesions, including adenomas and carcinomas, focal areas of high-grade dysplasia (FAD), and polypoid hyperplasias with FADS. The incidence of inherited colonic neoplasms has now been modulated by a chemopreventive regimen. Colonic lesions significantly increased in Apc1638 mice on a Western-style diet, which has higher fat content and lower calcium and vitamin D compared to the same mice on AIN-76A diet. In another rodent model, Min mice were treated with sulindac, which markedly reduced the incidence of intestinal tumors. A third new rodent model containing a targeted mutation in the gene Mcc (mutated in colorectal cancer) recently became available for chemoprevention studies. These mice develop multiple types of neoplasms including adenocarcinomas, focal areas of gastrointestinal dysplasia, papillomas of the forestomach, and tumors in other organs including lung, liver, and lymphoid tissue. Feeding a Western-style diet to the Mcc mutant mice also resulted in significantly increased gastrointestinal lesions. These nutrient modifications also have been given to normal mice, demonstrating without any chemical carcinogen that a Western-style diet induced colonic tumorigenesis. Western-style diets also have now induced modulation of cell proliferation in other organs including mammary gland, pancreas, and prostate. These findings help develop new preclinical rodent models to aid the analysis of genetic and environmental factors leading to neoplasia, as well as new methods for evaluating the chemopreventive efficacy of specific nutrients and pharmacological agents.

Animals↗

PubMed1986

Multi-type Galton-Watson process as a model for proliferating human tumour cell populations derived from stem cells: estimation of stem cell self-renewal probabilities in human ovarian carcinomas.

A mathematical model for proliferation of tumour cell populations is developed. The cell population is assumed to be organized in a hierarchy of decreasing proliferative potential and increasing degree of differentiation. Using some elements of the theory of Multi-type Galton-Watson processes, a method is proposed for the estimation of Psr, the probability of self-renewal of tumour stem cells, from the experimental distribution of clonal unit sizes obtained in cell culture studies. Six data sets from patients with advanced adenocarcinoma of the ovary are used to demonstrate the method. Reasonable estimates are obtained, and the theoretical colony size distributions predicted by the model appear to be in good qualitative agreement with the experimental ones, and lend support to a stem cell model of tumour growth. The possible significance of Psr as a prognostic factor is briefly discussed.

Cell Division↗

PubMed1998

Molecular characterisation of a novel plant homeobox gene expressed in the maturing xylem zone of Populus tremula x tremuloides.

In trees, wood is produced from the vascular cambium. However, little is known about how differentiation of the cambial derivatives is controlled at the molecular level. Hybrid aspen, Populus tremula x tremuloides, is a fast-growing, wood-forming plant from which an efficient transformation and regeneration protocol has been developed. We use this species as a model to study xylem cell differentiation. In a cross-section of the stem, cells in the cambial region at different stages of development can be seen in a radial distribution. We dissected out the cambial region and constructed a cDNA-library from this tissue. The library was screened with a degenerated primer mix complementary to the third helix region of the homeobox. A number of cDNAs hybridising to the probe were isolated, purified, cloned and sequenced. Characterisation of the expression pattern of two such homeobox cDNAs revealed that one of the cDNAs, denoted PttHB1, was specifically expressed in the xylem maturation zone, indicating a role in the regulation of secondary wall formation, while the other, denoted PttHB2 was expressed in differentiating xylem and phloem cells. Structurally, the two hybrid aspen homeobox genes are homologous to each other, but no close relationship could be identified between these genes and any other homeobox sequence described thus far, in plants or other eukaryotes. We therefore conclude that the PttHB1 and PttHB2 genes belong to a novel hitherto undescribed sequence class of homeobox genes. We designate this as PALE.

Amino Acid Sequence↗

PubMed2026

Cell-of-origin Discovery in Infant Leukemia through Integration of 3D Models and Patient Transcriptomic Data.

Pediatric hematological malignancies remain challenging to investigate and model due to the age group-specificity of certain genetic abnormalities. In utero origin has been demonstrated for a subset of pediatric leukemias, placing their respective cell of origin (CoO) during embryonic development. We recently reported a 3D hemogenic gastruloid (haemGx) model of embryonic blood formation derived from mouse embryonic stem cells, resolving the spatio-temporal complexity of developmental hematopoiesis. Importantly, it allows genetic engineering to introduce disease-relevant mutations. Using haemGx, we modeled the most common acute myeloid leukemia exclusive to infants (infAML), subtype t(7;12)(q36;p13), which arises in utero and is characterized by MNX1 overexpression. Here, we detail a method to define susceptibility to specific mutations that integrate phenotypic and transcriptional changes in the haemGx system and compares them with patient data. By proxy of our MNX1-overexpression haemGx, we show a pipeline from cell engineering to downstream analyses of leukemogenic potential. In particular, we focus on the clinical relevance of the model by integrating single-cell and/or bulk RNA sequencing from the haemGx platform with patient data to extract cellular composition and temporal placement of the putative CoO. This method is adaptable to the introduction of other oncogenic mutations, chromosomal rearrangements, or epigenetic modifications, as well as to chemical perturbations, including drug vulnerability and growth factor dependence. This flexibility allows for broad application across diverse disease contexts, enabling mechanistic dissection of how specific alterations disrupt early developmental trajectories with clinical relevance.

Humans↗

PubMed2002

Embryonic stem cells provide a powerful and versatile model system.

Embryonic stem (ES) cells are pluripotent stem cells that differentiate both in vitro and in vivo into cell types derived from each of the three embryonic germ layers. ES cells and their close relatives, embryonal carcinoma (EC) cells and embryonic germ (EG) cells, have been used extensively as model systems for studying early mammalian development. This work has led to important insights into the mechanisms that control embryogenesis at the molecular and cellular levels. This chapter focuses on the use of ES cells as an in vitro model system for studying cellular differentiation and reviews several areas where important progress has been made. Impressive progress has been made in the isolation and characterization of ES cells from many species, including humans. Significant progress has also been made in the development of culture conditions that help direct the differentiation of ES cells to specific cell types that form during myogenesis, angiogenesis, hematopoiesis, neurogenesis, and cardiogenesis. The ability to inactivate virtually any gene in ES cells by gene targeting has vastly improved our understanding of the roles played by specific genes at the cellular and organismic levels. Moreover, ES cells and EC cells have been used widely to investigate how specific genes are turned on and turned off in the course of differentiation. In this connection, DNA array technology has been used to identify genes regulated when ES cells differentiate. The final section of this chapter discusses how work with ES cells is shaping our understanding of stem cells, mammalian development, and cell replacement therapy.

Animals↗

PubMed2006

The rationale for the IL-2-independent generation of the self-renewing central memory CD8+ T cells.

Clones of CD8+ T cells that have been selected in the primary response must have a mechanism by which they can continuously or intermittently generate new effector cells. Several years ago, this mechanism was proposed to involve a self-renewing, stem cell-like subset that could avoid the differentiating effects of interleukin-2 (IL-2). The model considered the stem cell subset to be contained within the central memory population of CD8+ T cells (T(CM)). This proposal was inconsistent with subsequent findings suggesting that all antigen-activated CD8+ T cells differentiated to effector cells (T(EFF)) during the primary response and that T(CM) developed during the memory phase by de-differentiating from effector memory cells (T(EM)). However, findings have since been reported that support the stem cell model. First, studies indicate that T(EM) do not serve as the precursors of T(CM). Second, transcriptional repressors of IL-2 signaling do enhance the memory response. Third, memory cells lacking effector functions and with a capacity to replicate in a secondary response develop in the absence of signaling through the IL-2/IL-15 receptor. Taken together, these findings suggest that antigen-activated CD8+ T cells with a stem cell-like capability for maintaining proliferative potential develop by an unknown IL-2-independent process. The challenge is now to identify this unknown pathway of clonal expansion.

Animals↗

PubMed2007

Chronic myeloid leukemia blast crisis arises from progenitors.

Chronic myeloid leukemia (CML) progresses through three distinct clinical stages: chronic phase, accelerated phase, and blast crisis. The progression to accelerated phase and blast crisis is driven by activation of oncogenes, inactivation of tumor suppressor genes, and/or amplification of the BCR-ABL fusion gene, which causes the chronic phase of the disease. The cell of origin of blast crisis is a subject of speculation. Here, I develop a simple mathematical model of CML blast crisis to investigate whether blasts arise from leukemic stem cells or more differentiated leukemic cells. I use data of patients treated with imatinib and previous agents to estimate the effects of therapy on the rate of progression. Imatinib reduces the progression rate 10-fold as compared with previous (ineffective) therapies. If blasts were produced by leukemic stem cells, there would be no difference in the rate of progression between patients treated with imatinib and previous therapies, because imatinib seems to be incapable of depleting leukemic stem cells. Imatinib does, however, deplete leukemic progenitors. Therefore, CML blasts are likely to arise from leukemic progenitors. Disclosure of potential conflicts of interest is found at the end of this article.

Benzamides↗

PubMed2003

Stem cells: a promising source of pancreatic islets for transplantation in type 1 diabetes.

Diabetes is a disease that affects millions and causes a major burden on the health care system. Type 1 diabetes has traditionally been managed with exogenous insulin therapy, however factors such as cost, lifestyle restriction, and life threatening complications necessitate the development of a more efficient treatment alternative. Pancreas transplantation, and more recently transplant of purified pancreatic islets, has offered the potential for independence from insulin injections. Islet transplantation is gaining acceptance as it has been shown to be effective for certain patients with type 1 diabetes. One obstacle, however, is the fact that there is an inadequate supply of cadaveric human islets to implement this procedure on a widespread clinical basis. A promising source of transplantable islets in the future will come through the use of adult or embryonic stem cells. This chapter presents an overview of the advancements made in the development of a stem cell based application to islet transplantation. Advantages and limitations are discussed regarding the use of embryonic stem cells, adult pancreatic stem/progenitor cells, and the use of nonpancreatic tissues based on current experimental models in the literature. It is concluded that stem cells offer the greatest potential for the development of an abundant source of pancreatic islets, although specific obstacles must be overcome before this can become a reality.

Animals↗

PubMed1997

Assay systems for hematopoietic stem and progenitor cells.

Progress in our understanding of the hematopoietic system as well as novel cellular and molecular biology techniques are increasingly promoting the ex vivo manipulation and therapeutic use of hematopoietic stem and progenitor cells. For both, development of stem cell therapies and basic hematopoietic research, test systems for hematopoietic stem cells are required to monitor the intrinsic and ex vivo-induced properties of these cells. In vitro assays for primitive hematopoietic cells (colony-forming units-blast, cobblestone area-forming cells, long-term culture-initiating cells [LTC-IC]) have been established which demonstrate the proliferative and differentiation capacities of these populations. The potentials of these assays have been recently enhanced by the extended LTC and the switch LTC modifications. Although some hematopoietic cells characterized in vitro have the multipotential and proliferative properties of pluripotent hematopoietic stem cells (PHSC), their capacity to long-term repopulate hematopoiesis in vivo, a hallmark of PHSC, has not been established. Without this confirmation, populations defined in vitro should not be considered the equivalent of PHSC. In animals, the properties of primitive hematopoietic cells can be systematically analyzed by multiple in vivo assays. Therefore, various strategies have been pursued to develop an animal model for human hematopoiesis. In fetal sheep and immunodeficient mice, the functions of human PHSC are reproduced, and long-term multilineage repopulation capacity and extensive proliferative potential have been demonstrated for xenografted human cells. Thus, both models can be considered stem cell assays and may significantly enhance the study of early hematopoiesis and the development of therapeutic strategies.

Animals↗

PubMed2006

Multipotent flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages.

Cell-tracing studies in the mouse indicate that the cardiac lineage arises from a population that expresses the vascular endothelial growth factor receptor 2 (VEGFR2, Flk-1), suggesting that it may develop from a progenitor with vascular potential. Using the embryonic stem (ES) cell differentiation model, we have identified a cardiovascular progenitor based on the temporal expression of the primitive streak (PS) marker brachyury and Flk-1. Comparable progenitors could also be isolated from head-fold stage embryos. When cultured with cytokines known to function during cardiogenesis, individual cardiovascular progenitors generated colonies that displayed cardiomyocyte, endothelial, and vascular smooth muscle (VSM) potential. Isolation and characterization of this previously unidentified population suggests that the mammalian cardiovascular system develops from multipotential progenitors.

Animals↗

PubMed2004

A genetic progression model of oral cancer: current evidence and clinical implications.

Based on recent genetic studies, we propose a progression model for the development of oral squamous cell carcinoma. In the initial phase, a stem cell acquires a genetic alteration; subsequently a patch is formed, a clonal unit consisting of the stem cell with its daughter cells that all share the DNA alteration. The next critical step is the conversion of a patch into an expanding field as a result of additional genetic alterations. This mucosal field replaces the normal epithelium and in the oral cavity such fields have been detected with dimensions of over 7 cm in diameter. Sometimes these fields are visible as leukoplakia. Ultimately, clonal selection leads to the development of carcinoma within this contiguous field of pre-neoplastic cells. An important clinical implication of this model is that fields often remain after surgery of the primary tumor and may lead to new cancers, presently designated by clinicians as second primary tumors or local recurrences.

Carcinoma, Squamous Cell↗

PubMed2003

Correction of a mouse model of sickle cell disease: lentiviral/antisickling beta-globin gene transduction of unmobilized, purified hematopoietic stem cells.

Although sickle cell anemia was the first hereditary disease to be understood at the molecular level, there is still no adequate long-term treatment. Allogeneic bone marrow transplantation is the only available cure, but this procedure is limited to a minority of patients with an available, histocompatible donor. Autologous transplantation of bone marrow stem cells that are transduced with a stably expressed, antisickling globin gene would benefit a majority of patients with sickle cell disease. Therefore, the development of a gene therapy protocol that corrects the disease in an animal model and is directly translatable to human patients is critical. A method is described in which unmobilized, highly purified bone marrow stem cells are transduced with a minimum amount of self-inactivating (SIN) lentiviral vector containing a potent antisickling beta-globin gene. These cells, which were transduced in the absence of cytokine stimulation, fully reconstitute irradiated recipients and correct the hemolytic anemia and organ pathology that characterize the disease in humans. The mean increase of hemoglobin concentration was 46 g/L (4.6 g/dL) and the average lentiviral copy number was 2.2; therefore, a 21-g/L /vector copy increase (2.1-g/dL) was achieved. This transduction protocol may be directly translatable to patients with sickle cell disease who cannot tolerate current bone marrow mobilization procedures and may not safely be exposed to large viral loads.

Anemia, Sickle Cell↗