Showing papers on "Cellular differentiation published in 1983"
TL;DR: It is concluded that the cell lineage itself, complex as it is, plays an important role in determining cell fate and is demonstrated to demonstrate substantial cell autonomy in at least some sections of embryogenesis.
3,938 citations
Journal Article•
TL;DR: It has been known for more than 50 years that retinoids, the family of molecules comprising both the natural and synthetic analogues of retinol, are potent agents for control of both cellular differentiation and cellular proliferation as discussed by the authors.
Abstract: It has been known for more than 50 years that retinoids, the family of molecules comprising both the natural and synthetic analogues of retinol, are potent agents for control of both cellular differentiation and cellular proliferation (70). In their original clas sic paper describing the cellular effects of vitamin A deficiency in the rat, Wolbach and Howe clearly noted that there were distinct effects on both differentiation and proliferation of epithelial cells. During vitamin A deficiency, it was found that proper differentia tion of stem cells into mature epithelial cells failed to occur and that abnormal cellular differentiation, characterized in particular by excessive accumulation of keratin, was a frequent event. Furthermore, it was noted that there was excessive cellular proliferation in many of the deficient epithelia. Although the conclusion that an adequate level of retinoid was necessary for control of normal cellular differentiation and proliferation was clearly stated in the original paper by Wolbach and Howe, a satisfactory explanation of the molecular mechanisms underlying these effects on both differentiation and proliferation still eludes us more than 50 years later. It was inevitable that the basic role of retinoids in control of cell differentiation and proliferation would eventually find practical application in the cancer field, and there have been great ad vances in this area, particularly for prevention of cancer. Many studies have shown that retinoids can suppress the process of carcinogenesis in vivo in experimental animals (for reviews, see Refs. 7, 33, 51, 54, 56, and 57), and these results are now the basis of current attempts to use retinoids for cancer prevention in humans. Furthermore, there is now an extensive literature on the ability of retinoids to suppress the development of the malignant phenotype in vitro (for reviews, see Refs. 6, 8, 30, and 31 ), and these studies corroborate the use of retinoids for cancer prevention. Finally, most recently, it has been shown that reti noids can exert effects on certain fully transformed, invasive, neoplastic cells, leading in certain instances to a suppression of proliferation (30) and in other instances to terminal differentiation of these cells, resulting in a more benign, nonneoplastic pheno type (10,11,60,62). Even though there are many types of tumor cells for which this is not the case (33, 52) (indeed, at present there are only a limited number of instances in which such profound effects of retinoids on differentiation and proliferation of invasive tumor cells have been shown), this finding neverthe less has highly significant implications for the problem of cancer treatment. It emphasizes that in many respects cancer is fun damentally a disease of abnormal cell differentiation (36,44), and it raises the possibility that even invasive disease may eventually be controlled by agents which control cell differentiation rather than kill cells. Since carcinogenesis is essentially a disorder of cell differentiation, the overall scientific problem of the role of retinoids in either differentiation or carcinogenesis is essentially
824 citations
TL;DR: It is proposed that lin-12 functions as a binary switch to control decisions between alternative cell fates during C. elegans development.
569 citations
TL;DR: A review critically examines the inducers of leukemic cell differentiation and their potential therapeutic importance in patients with acute myelogenous leukemia.
552 citations
TL;DR: DNA sequences containing the 5′-flanking regions of the insulin and chymotrypsin genes were linked to the coding sequence of the chloramphenicol acetyltransferase (CAT) gene, which elicits preferential expression of CAT activity when introduced into cells producing insulin.
Abstract: DNA sequences containing the 5′-flanking regions of the insulin and chymotrypsin genes were linked to the coding sequence of the chloramphenicol acetyltransferase (CAT) gene. The insulin gene recombinant elicits preferential expression of CAT activity when introduced into cells producing insulin; similarly, the chymotrypsin gene recombinant elicits preferential expression in chymotrypsin-producing cells. Sequences located upstream of previously defined transcriptional control elements are essential for efficient expression in both cases.
538 citations
TL;DR: It seems appropriate to call these neoplasms primitive neuroectodermal tumors and to use descriptive terms to indicate the direction of cellular differentiation, when it has occurred.
Abstract: A simple classification system for central nervous system neoplasms occurring primarily in infancy and childhood and largely composed of undifferentiated neuroepithelial cells is proposed. Classification is based upon appearance of the tumor as determined by light microscopy, immunocytochemical techniques, and ultrastructural features without consideration for site of origin. This classification is based on the concept that neoplastic transformation of primitive neuroepithelial cells in subependymal zones at all levels of the central nervous system or pineal body may develop into tumors largely composed of similar cells. It therefore seems appropriate to call these neoplasms primitive neuroectodermal tumors and to use descriptive terms to indicate the direction of cellular differentiation, when it has occurred. Proposed terminology for the five subtypes of undifferentiated neuroepithelial round cell tumors is as follows: 1) Primitive neuroectodermal tumor, not otherwise specified (PNET, NOS), 2) PNET with glial differentiation, 3) PNET with ependymal differentiation, 4) PNET with neuronal differentiation, and 5) PNET with multi- or bipotential differentiation. If the tumor is located in the cerebellum, medulloblastoma may be added in parentheses; if in the pineal body, pineal parenchymal neoplasm may be added.
494 citations
TL;DR: The isolation and characterization of several monoclonal antibodies to the B lineage-specific surface molecule, B220, which was shown to be expressed on precursors of B cells by the demonstration that removal of B220+ cells from B cell-depleted bone marrow removes the ability of bone marrow to regenerate B cells.
Abstract: The first part of this article discusses the isolation and characterization of several monoclonal antibodies to the B lineage-specific surface molecule, B220. B220 was shown to be expressed on precursors of B cells by the demonstration that removal of B220+ cells from B cell-depleted bone marrow removes the ability of bone marrow to regenerate B cells. Although these antibodies recognize a broad range of differentiation stages within the B lineage, they can be used to isolate highly enriched populations of pre-B cells from mouse bone marrow. We also describe the use of antibodies to the surface markers B220 and ThB to define two sequential stages of pre-B cell differentiation. A simplified diagram of our current view of the B lineage differentiation sequence is shown in Figure 4. No attempt has been made to include the various functionally defined B cell subsets on this diagram since we know almost nothing about the expression of these two surface markers on them. This model reflects an assumption that the early part of B cell differentiation is a linear rather than a branching pathway. At present, there is no evidence for a branching pathway, but little evidence against it either. B220 is the first B cell-specific molecule known to be expressed during differentiation and it continues to be expressed on most subsequent B lineage cells. In this regard, it resembles the Thy-1 molecule on thymus-derived lymphocytes and, like Thy-1, B220 should be quite useful for identifying and classifying B lineage cells. One example of this is the use of B220 expression to clearly assign germinal center cells to the B lineage. The example of Thy-1+, RA3-2C2+ cells from mice with the lpr/lpr genotype, however, suggests that some caution should be used when interpreting data, especially with pathological samples. The availability of substantially purified pre-B cell populations has made it possible to follow changes in immunoglobulin gene organization and expression during differentiation. Our current understanding of these events is also shown in Figure 4, correlated with cell surface phenotype. The large pre-B cell population has extensive heavy chain rearrangements and synthesizes significant quantities of mu heavy chain, but does not yet have detectable light chain gene rearrangement. The small pre-B population consists of two cell types, some with kappa gene rearrangement and some without. This suggests that kappa rearrangement occurs within this cell population, which is homogeneous with respect to morphology and surface phenotype. The asynchrony of heavy and light chain gene rearrangement results in an asynchrony at the level of expression of these genes as well, but the purpose of this remains one of many unanswered questions about pre-B cell differentiation. Now that it is possible to identify, isolate, and manipulate pre-B cells as readily as B or T cells, many of these questions may now be addressed.
471 citations
TL;DR: This work believes this to be the first demonstration of a sequential relationship between the application of an exogenous inducing agent, a reduction in myc mRNA levels and the development of characteristics associated with normal cell maturation.
Abstract: HL-60, a cell line established from a patient with promyelocytic leukaemia, responds to a variety of inducing agents by ceasing division and acquiring some of the characteristics of either granulocytes or monocytes. Among the agents so far tested, only a comparative few occur naturally in vertebrates and would appear to have significant clinical potential in the treatment of leukaemic patients. One of the most promising of these is the dihydroxymetabolite of vitamin D3, 1,25(OH)2D3. This compound circulates in normal man and has a major role in calcium homeostasis. Moreover, it has recently been reported that 1,25(OH)2D3 increases the survival time of mice injected with myeloid leukaemia cells. We and McCarthy et al. have previously shown that HL-60 cells respond to near physiological levels of 1,25(OH)2D3 by rapidly acquiring a number of monocyte-like features. Here we document that these phenotypic changes are preceded by a marked decrement in the expression of the c-myc oncogene. In fact, the diminution in the level of c-myc mRNA parallels the dose dependency and metabolite specificity shown by the various other indicators of phenotypic change. In addition, we demonstrate that removal of vitamin D3, after the onset of maturational change, results in the reappearance of elevated myc mRNA levels. We believe this to be the first demonstration of a sequential relationship between the application of an exogenous inducing agent, a reduction in myc mRNA levels and the development of characteristics associated with normal cell maturation.
469 citations
TL;DR: This work has used a variety of techniques to determine the cellular and structural basis for certain of these end bud activities of mammary ductal morphogenesis and elongation in the immature mouse.
468 citations
TL;DR: It is demonstrated that fibronectin can regulate gene expression for lipogenic proteins and it is suggested that it interferes with cytoskeletal and morphological changes necessary for new gene expression.
431 citations
Journal Article•
TL;DR: The results strongly suggest that certain cells other than helper T cells and thymocytes can express and, at least in some cases, synthesize a component previously regarded as T-lineage specific.
Abstract: Anti-Leu-3a, anti-Leu-3b, OKT4, and anti-T4 murine monoclonal antibodies react with a membrane component expressed by mature peripheral blood helper T cells and certain thymocyte subsets. Using a variety of immunologic staining techniques, we have demonstrated the reactivity of these antibodies with other cell types. Normal and neoplastic cells of monocyte/macrophage lineage bear the Ia+/Leu-6-/Leu-3+ phenotype, whereas histiocytosis X cells bear the Ia+/Leu-6+/Leu-3+ phenotype. The Ia+/Leu-6- cells of malignant histiocytosis and the Ia+/Leu-6+ epidermal Langerhans cells were variably Leu-3+. Normal monocyte/macrophage reactivity with anti-Leu-3/T4 appears to be primarily intracytoplasmic, whereas on U937 monocyte tumor cells, marked membrane reactivity is also observed. These results strongly suggest that certain cells other than helper T cells and thymocytes can express and, at least in some cases, synthesize a component previously regarded as T-lineage specific.
TL;DR: The developing knowledge of the biochemistry and mode of action of the lymphokines that act upon B cells include distinct growth and differentiation factors, which should lead to a new physiologically-based pharmacology for manipulation of antibody responses in human disease and in responses to vaccines.
Abstract: The B-lymphocyte family of cells presents one of the most remarkable opportunities for the detailed study of regulation of growth and differentiation. Some members of this cell population have the property that they may be stimulated by ligand-receptor interactions, together with the sequential action of a series of lymphokines, to progress from the resting state, through several rounds of proliferation, and then to differentiate to immunoglobulin secretion. Other cells in this group participate in cognate cellular interactions with helper T cells in which the recognition of both antigen and a class II MHC molecule on the B-cell surface is key to activation. The differentiation of these cells is also controlled by soluble products. We have reviewed our developing knowledge of the biochemistry and mode of action of the lymphokines that act upon B cells. These include distinct growth and differentiation factors. Among these are the BCGFs of mice and humans and the various TRFs, which include molecules often described as differentiation factors. The next several years should witness major progress in understanding the physicochemical properties of the B cell-specific factors, their time and nature of action, and the nature of their receptors. In addition, we can anticipate a major effort to understand the intracellular events that flow from the action of specific growth and differentiation factors that act upon B cells. Such information should lead to a new physiologically-based pharmacology for manipulation of antibody responses in human disease and in responses to vaccines. In addition, the fuller understanding of the nature and mode of action of the various growth and differentiation factors should make long-term growth of cloned B cells a procedure that can be routinely used in immunological laboratories for the precise study of the biology of responses by homogeneous populations of B lymphocytes.
TL;DR: Using an immunohistochemical method to localize the mouse macrophage specific antigen F4/80, this paper showed that macrophages migrate from the vascular supply overlying the developing retina and phagocytose the degenerating neurons.
Abstract: In the developing mouse retina degenerating neurons can be observed initially in the ganglion cell layer followed by a phase of cell death in the inner nuclear layer. Using an immunohistochemical method to localize the mouse macrophage specific antigen F4/80, we show that macrophages migrate from the vascular supply overlying the developing retina and phagocytose the degenerating neurons. The macrophages subsequently differentiate to become the microglia of the retina and form a regularly spaced distribution across the retina in the inner and outer plexiform layers. These experiments provide strong evidence for the mesodermal origin of central nervous system microglia.
TL;DR: It is shown that the 70K early two-cell-specific proteins are identical to two of the mouse heat shock proteins, HSP 68 and HSP 70.
Abstract: In many species, the early post-fertilization development of the egg appears to occur mainly under maternal control and does not require transcription of the embryonic genome. In the mouse this situation is restricted to the one-cell stage; activation of the embryonic genome occurs at the late two-cell stage and results in a drastic change in the spectrum of proteins synthesized. This activation is preceded by a decrease in the overall synthesis of proteins at the end of the one-cell stage and the appearance, at the early two-cell stage, of a set of new polypeptides of molecular weight approximately 70,000 (70K) (refs 2, 8, 9). This can be compared with the series of events that occur after hyperthermia in differentiated cells. Heat shock results in an arrest of most transcription and translation; subsequently, expression of a limited set of genes, the heat shock genes, precedes the overall reactivation of cellular genome. Here we show that the 70K early two-cell-specific proteins are identical to two of the mouse heat shock proteins, HSP 68 and HSP 70.
TL;DR: A mutant clone which does not differentiate in the presence of any of the drugs which are normally effective in inducing differentiation of P19 cells is isolated and may help to elucidate the chain of events triggered by retinoic acid and other differentiation-inducing drugs.
Abstract: We have previously shown that the P19 line of embryonal carcinoma cells develops into neurons, astroglia, and fibroblasts after aggregation and exposure to retinoic acid. The neurons were initially identified by their morphology and by the presence of neurofilaments within their cytoplasm. We have more fully documented the neuronal nature of these cells by showing that their cell surfaces display tetanus toxin receptors, a neuronal cell marker, and that choline acetyl-transferase and acetyl cholinesterase activities appear coordinately in neuron-containing cultures. Several days before the appearance of neurons, there is a marked decrease in the amount of an embryonal carcinoma surface antigen, and at the same time there is a substantial decrease in the volumes of individual cells. Various retinoids were able to induce the development of neurons in cultures of aggregated P19 cells, but it did not appear that polyamine metabolism was involved in the effect. We have isolated a mutant clone which does not differentiate in the presence of any of the drugs which are normally effective in inducing differentiation of P19 cells. This mutant and others may help to elucidate the chain of events triggered by retinoic acid and other differentiation-inducing drugs.
TL;DR: Evidence in favor of the existence of skin-associated lymphoid tissues (SALT) includes that the cutaneous microenvironment is capable on its own of accepting, processing, and presenting nominal antigen, and subsets of T lymphocytes display differential affinity for skin and its associated peripheral nodes.
TL;DR: Findings suggest that, as a histological group, human neuroblastoma cells are extremely sensitive to RA-induced growth inhibition and morphological alterations generally associated with reduced expression of the malignant phenotype of this type of cancer.
TL;DR: Gangliosides may regulate cell growth and nerve sprouting, suggesting the potential therapeutic value for some neurological disorders and current ganglioside research is more rapidly growing largely due to advancing methodologies.
TL;DR: A series of monoclonal antibodies that reacts with myeloids-associated determinants on committed myeloid stem cells and their progeny are generated and potential applications of these antibodies to studies of normal and malignant hematopoiesis are discussed.
TL;DR: Lectin binding to different cell layers in natural and cultured human epidermis is investigated, and the binding of peanut agglutinin shows interesting correlations with involucrin expression, both in stratified colonies and in monolayers.
TL;DR: The results suggest that the reciprocal regulations of cell growth and hepatocyte-specific functions are mediated by some surface components via cell-cell contact.
Abstract: In primary monolayer cultures of rat mature hepatocytes, many metabolic functions as well as cell growth are regulated by cell density. There are two types of regulatory response of these functions to change of cell density. Growth-related functions, such as DNA synthesis, induction of glucose-6-phosphate dehydrogenase, 2-aminoisobutyric acid transport, synthesis of cellular protein, and cholesterogenesis, are stimulated by low cell density. In contrast, functions related to hepatocyte-specific characters, such as the inductions of tyrosine aminotransferase, serine dehydratase, and malic enzyme and synthesis of triglycerides, are stimulated by high cell density. The reciprocal responses of these cellular activities to cell density were mimicked by addition of plasma membranes purified from adult rat liver to hepatocytes cultured at low cell density. The modulator activity was heat labile and trypsin sensitive. The activity was also found in plasma membranes from kidney, brain, and erythrocytes, although the specific activities of these preparations seemed to be different. These results suggest that the reciprocal regulations of cell growth and hepatocyte-specific functions are mediated by some surface components via cell-cell contact.
TL;DR: The results suggest that during normal embryogenesis, the commitment of pluripotent cells to particular developmental avenues may be determined in part by concentration gradients of substances such as retinoids.
Journal Article•
TL;DR: Some clones of the human histiocytic lymphoma line, U-937, were induced to differentiate into monocyte-like cells with loss of plating efficiency in agar by incubation with 0.1 to 10 nM 1 alpha,25-dihydroxycholecalciferol [1,25(OH)2D3].
Abstract: Some clones of the human histiocytic lymphoma line, U-937, were induced to differentiate into monocyte-like cells with loss of plating efficiency in agar by incubation with 0.1 to 10 nM 1 alpha,25-dihydroxycholecalciferol [1,25(OH)2D3]. At 1 nM, 40% of the cells of one sensitive clone exhibited differentiation after 2 days of incubation judging from assays for phagocytosis and capacity to reduce nitroblue tetrazolium. Induction appeared to occur by binding of the cholecalciferol to a specific cytoplasmic and/or nuclear receptor for 1,25(OH)2D3. However, the presence of this receptor was not sufficient for differentiation, since one clone which contained the receptor did not respond with differentiation upon addition of 1,25(OH)2D3. Differentiation induction did not require DNA synthesis but was blocked by agents which inhibit RNA or protein synthesis. It was also blocked by the calcium ionophore A 23187. A synergistic inducing effect was seen between 1,25(OH)2D3 and retinoic acid. In addition, the U-937 cells could be primed by a short incubation with 1,25(OH)2D3 to respond, with maturation, to the addition of agents which increase the intracellular level of cyclic adenosine 3':5'-monophosphate, such as prostaglandin E2, cholera toxin, and N6,O2'-dibutyryl adenosine 3':5'-monophosphate and which alone did not induce differentiation. Priming does not depend on the normal rate of RNA or protein synthesis, since it was not significantly inhibited by actinomycin D, cordycepin, or cycloheximide. It remains to be determined if unoccupied receptors for 1,25(OH)2D3 are present in fresh leukemia cells and if such cells can sometimes be induced to differentiate upon addition of cholecalciferol.
TL;DR: It is reported here that human thyroid follicular cells which are normally negative for HLA-DR molecules, can be induced to express these antigens when cultured with phytohaemagglutinin (PHA), concanavalin A (Con A) or pokeweed mitogen (PWM).
Abstract: HLA-DR antigens, the human equivalent of mouse I region-associated or Ia products, are polymorphic cell surface sialoglycoproteins involved in initiation of the immune response1. Their expression is normally restricted to B lymphocytes, macrophages, dendritic and other antigen-presenting cells and vascular endothelium2 and possibly some cells of the mucosa lining body cavities3,4. HLA-DR expression can be modified during cell differentiation; B lymphocytes become negative on maturing to plasma cells and human T lymphocytes acquire these antigens when activated in vitro or in vivo5. We report here that human thyroid follicular cells which are normally negative for HLA-DR molecules, can be induced to express these antigens when cultured with phytohaemagglutinin (PHA), concanavalin A (Con A) or pokeweed mitogen (PWM). These lectins exert their action directly on the thyroid cells with no concomitant mitogenic effect.
TL;DR: G-CSF has been shown to stimulate the initial proliferation of a large proportion of the granulocyte-macrophage progenitors in adult marrow and also the survival and/or proliferation of some multipotential, erythroid, and eosinophil progenitor cells in fetal liver.
Abstract: When granulocyte colony-stimulating factor (G-CSF), purified to homogeneity from mouse lung-conditioned medium, was added to agar cultures of mouse bone marrow cells, it stimulated the formation of small numbers of granulocytic colonies. At high concentrations of G-CSF, a small proportion of macrophage and granulocyte-macrophage colonies also developed. G-CSF stimulated colony formation by highly enriched progenitor cell populations obtained by fractionation of mouse fetal liver cells using a fluorescence-activated cell sorter, indicating that G-CSF probably acts directly on target progenitor cells. Granulocytic colonies stimulated by G-CSF were small and uniform in size, and at 7 days of culture were composed of highly differentiated cells. Studies using clonal transfer and the delayed addition of other regulators showed that G-CSF could directly stimulate the initial proliferation of a large proportion of the granulocyte-macrophage progenitors in adult marrow and also the survival and/or proliferation of some multipotential, erythroid, and eosinophil progenitors in fetal liver. However, G-CSF was unable to sustain continued proliferation of these cells to result in colony formation. When G-CSF was mixed with purified granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF), the combination stimulated the formation by adult marrow cells of more granulocyte-macrophage colonies than either stimulus alone and an overall size increase in all colonies. G-CSF behaves as a predominantly granulopoietic stimulating factor but has some capacity to stimulate the initial proliferation of the same wide range of progenitor cells as that stimulated by GM-CSF.
TL;DR: The lectin receptors are characteristic markers of distinct lymphocyte subpopulations in mouse, man, and several other animals and are extremely useful for the identification and separation of lymphocytes, and therefore for studies on the functions and lineages of cells with a given phenotype.
Abstract: Publisher Summary The lectin receptors are characteristic markers of distinct lymphocyte subpopulations in mouse, man, and several other animals. Just like antigenic surface markers, lectin receptors are extremely useful for the identification and separation of lymphocytes, and therefore for studies on the functions and lineages of cells with a given phenotype. Some of them may even be considered as differentiation markers. Purification procedures designed to recover a representative culture of lymphocytes from blood or other tissues may lead to the removal of less well-defined subpopulations of these cells. In addition, cell fractionation may lead to alterations in cellular constituents, as shown by the finding of a marked increase in potassium and a decrease in sodium ion content in isolated rat thymus cells and compared to the levels of these ions in rapidly excised whole thymus. Two lymphocyte subpopulations are easily distinguished in the thymus, one located in the cortex and the other in the medulla. The medullary thymocytes, which in the past could be isolated in sufficient quantities only from mice that had been treated with cortisone or radiation, comprise approximately 10% of the total number of thymus cells. It has also been reported that cortisone resistant thymocytes and spleen T cells are more negatively charged and have a higher content of sialic acid than unfractionated thymocytes.
TL;DR: Kidney development seems to require an orderly, synchronized development of the three cell lineages: the branching ureter, the induced, tubule-forming mesenchyme, and the invading endothelial cells of outside origin.
TL;DR: Rat hepatocytes isolated by enzymatic dissociation of the liver mu,st attach in order to survive for more than a few hours remain able to synthesize high levels of albumin and to conjugate drugs when co-cultured with a liver epithelial cell line, probably derived from biliary ductular cells.
Abstract: Rat hepatocytes isolated by enzymatic dissociation of the liver mu,st attach in order to survive for more than a few hours. In conventional culture conditions, they rapidly lose their highly differentiated functions, e.g. adult isozymic forms, enzyme response to specific hormones and cytochrome P-450-dependent monooxygenase activities. Incompletely differentiated cells such as perinatal and regenerating hepatocytes, can transiently exhibit a more differentiated state. Therefore, regulation of hepatic functions, particularly enzyme activities cannot be studied for more than a few days.
TL;DR: BALB or Kirsten murine sarcoma viruses are acute transforming retroviruses, which have been shown to transform fibroblastic and hematopoietic cells, and can rapidly confer upon epithelial keratinocytes in culture growth properties that resemble those of malignant epidermoid carcinoma cells.
TL;DR: Using a retrovirus vector, the transfer of a dominant selectable drug-resistance gene is demonstrated into defined classes of mouse haematopoietic progenitor cells to facilitate the development of molecular genetic approaches to fundamental and clinical problems in haem atopoiesis.
Abstract: The haematopoietic system is made up of a hierarchy of cells with different developmental, functional and proliferative capacities. Although cellular diversity appears to arise from the commitment and maturation of stem cells, the molecular basis for this differentiation process is unknown. The introduction of cloned DNA sequences into haematopoietic progenitor cells would provide a novel approach for studying this differentiating in vivo system. One laboratory has reported DNA-mediated transfer of genes into mouse bone marrow cells1,2. However, retroviruses offer a number of advantages over DNA-mediated gene transfer procedures, including high efficiency infection of a wide range of cell types in vitro and in vivo, stable and low copy integration into the host chromosome, and a defined integrated provirus structure. For these reasons recombinant DNA techniques have been utilized to construct high efficiency retrovirus vectors expressing foreign genes3–8. We demonstrate here, using such a retrovirus vector, the transfer of a dominant selectable drug-resistance gene into defined classes of mouse haematopoietic progenitor cells. These observations should facilitate the development of molecular genetic approaches to fundamental and clinical problems in haematopoiesis.