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At least 163 records · Page 9Linked to original sources
PubMed2005

Combining transfusion of stem/progenitor cells into the peripheral circulation with localized transplantation in situ at the site of tissue/organ damage: a possible strategy to optimize the efficacy of stem cell transplantation therapy.

Several studies have demonstrated the efficacy of localized in situ transplantation of stem/progenitor cells for tissue/organ regeneration. However, the possible limitations of such an approach have largely been overlooked. This is contrary to the intrinsic physiological process of tissue/organ regeneration in vivo, which is thought to involve the mobilization of stem/progenitor cells resident within the tissue/organ itself, as well as from ectopic sites, in particular the bone marrow. Signaling pathways and other molecular processes within stem/progenitor cells transplanted in situ may not be primed to achieve optimal tissue/organ regeneration, and may even be confused by the sudden rapid transition in the cellular microenvironment encountered during transplantation. To overcome these putative limitations, a possible strategy may be to combine transfusion of stem/progenitor cells into the peripheral circulation with localized transplantation in situ at the site of tissue/organ damage. This could better replicate the natural physiological process of tissue/organ repair in vivo. Possible synergistic interactions between the transplanted stem/progenitor cells in situ with migratory transfused cells from the peripheral circulation may further enhance tissue/organ regeneration. The transfused stem/progenitor cells may be induced to home in on a damaged tissue/organ, via the controlled release of specific cytokines or chemokines (i.e., SDF-1) emanating from that particular tissue/organ. There are a number of possible ways to achieve this. For example, the transplanted cells may be delivered on tissue-engineered scaffolds that are designed for the controlled release of specific homing factors such as SDF-1. Another alternative may be to stimulate or genetically modulate the transplanted cells to copiously secrete homing factors such as SDF-1, to encourage the migration and homing of transfused cells within the peripheral circulation. At the same time, it may also be advantageous to pre-stimulate the transfused cells to strongly express surface receptors specific to homing factors such as SDF-1, in particular CXCR-4. More rigorous investigations should be carried out on the possible strategy of combining in situ transplantation of stem/progenitor cells with transfusion into the peripheral circulation, together with induced homing of the transfused cells to the site of organ/tissue damage. This may possibly result in better efficacy for some, but not all models of tissue/organ regeneration.

Animals↗
PubMed2004

IR-inducible clusterin gene expression: a protein with potential roles in ionizing radiation-induced adaptive responses, genomic instability, and bystander effects.

Clusterin (CLU) plays numerous roles in mammalian cells after stress. A review of the recent literature strongly suggests potential roles for CLU proteins in low dose ionizing radiation (IR)-inducible adaptive responses, bystander effects, and delayed death and genomic instability. Its most striking and evident feature is the inducibility of the CLU promoter after low, as well as high, doses of IR. Two major forms of CLU, secreted (sCLU) and nuclear (nCLU), possess opposite functions in cellular responses to IR: sCLU is cytoprotective, whereas nCLU (a byproduct of alternative splicing) is a pro-death factor. Recent studies from our laboratory and others demonstrated that down-regulation of sCLU by specific siRNA increased cytotoxic responses to chemotherapy and IR. sCLU was induced after low non-toxic doses of IR (0.02-0.5 Gy) in human cultured cells and in mice in vivo. The low dose inducibility of this survival protein suggests a possible role for sCLU in radiation adaptive responses, characterized by increased cell radioresistance after exposure to low adapting IR doses. Although it is still unclear whether the adaptive response is beneficial or not to cells, survival of damaged cells after IR may lead to genomic instability in the descendants of surviving cells. Recent studies indicate a link between sCLU accumulation and cancer incidence, as well as aging, supporting involvement of the protein in the development of genomic instability. Secreted after IR, sCLU may also alter intracellular communication due to its ability to bind cell surface receptors, such as the TGF-beta receptors (types I and II). This interference with signaling pathways may contribute to IR-induced bystander effects. We hypothesize that activation of the TGF-beta signaling pathway, which often occurs after IR exposure, can in turn activate the CLU promoter. TGF-beta and IR-inducible de novo synthesized sCLU may then bind the TGF-beta receptors and suppress downstream growth arrest signaling. This complicated negative feedback regulation most certainly depends on the cellular microenvironment, but undoubtedly represents a potential link between IR-induced adaptive responses, genomic instability and bystander effects. Further elucidation of clusterin protein functions in IR responses are clearly warranted.

Animals↗
PubMed2005

Lysyl oxidase in development, aging and pathologies of the skin.

Lysyl oxidase (LOX) is a copper- and lysyl-tyrosyl cofactor containing amine oxidase that has been known to play a critical role in the catalysis of lysine-derived crosslinks in extracellular matrix (ECM) proteins in the dermis. Changes in the composition and crosslinked state of the ECM and alterations in LOX synthesis and activity are known to be associated with aging and a range of acquired and heritable skin disorders. It has been assumed until recently that the LOX-related changes in the skin are mediated through the catalytic activity of LOX. However, work by several laboratories over the last few years has shown that LOX is a multifunctional protein. In this review we discuss the regulation of expression, localization and activation of LOX in the normal developing and adult skin, and alterations in LOX expression and activity associated with skin aging and senescence, and in pathological conditions, including wound healing, fibrosis, hypertrophic scarring, keloids, scleroderma, and diabetic skin. We further evaluate the role of LOX in skin ECM changes associated with the normal aging process and with these pathological states. In addition to collagen and elastin cross-linkages, regulatory and activation mechanisms and cell type specific LOX interactions may contribute to a range of novel intra- and extracellular LOX functions that appear critical determinants of the cellular microenvironment in the normal skin and in these skin disorders.

Adult↗
PubMed2005

The RNA helicase DDX1 is involved in restricted HIV-1 Rev function in human astrocytes.

Productive infection by human immunodeficiency virus type I (HIV-1) in the central nervous system (CNS) involves mainly macrophages and microglial cells. A frequency of less than 10% of human astrocytes is estimated to be infectable with HIV-1. Nonetheless, this relatively low percentage of infected astrocytes, but associated with a large total number of astrocytic cells in the CNS, makes human astrocytes a critical part in the analyses of potential HIV-1 reservoirs in vivo. Investigations in astrocytic cell lines and primary human fetal astrocytes revealed that limited HIV-1 replication in these cells resulted from low-level viral entry, transcription, viral protein processing, and virion maturation. Of note, a low ratio of unspliced versus spliced HIV-1-specific RNA was also investigated, as Rev appeared to act aberrantly in astrocytes, via loss of nuclear and/or nucleolar localization and diminished Rev-mediated function. Host cellular machinery enabling Rev function has become critical for elucidation of diminished Rev activity, especially for those factors leading to RNA metabolism. We have recently identified a DEAD-box protein, DDX1, as a Rev cellular co-factor and now have explored its potential importance in astrocytes. Cells were infected with HIV-1 pseudotyped with envelope glycoproteins of amphotropic murine leukemia viruses (MLV). Semi-quantitative reverse transcriptase-polymerase chain reactions (RT-PCR) for unspliced, singly-spliced, and multiply-spliced RNA clearly showed a lower ratio of unspliced/singly-spliced over multiply-spliced HIV-1-specific RNA in human astrocytes as compared to Rev-permissive, non-glial control cells. As well, the cellular localization of Rev in astrocytes was cytoplasmically dominant as compared to that of Rev-permissive, non-glial controls. This endogenous level of DDX1 expression in astrocytes was demonstrated directly to lead to a shift of Rev sub-cellular distribution dominance from nuclear and/or nucleolar to cytoplasmic, as input of exogenous DDX1 significantly altered both Rev sub-cellular localization from cytoplasmic to nuclear predominance and concomitantly increased HIV-1 viral production in these human astrocytes. We conclude that altered DDX1 expression in human astrocytes is, at least in part, responsible for the unfavorable cellular microenvironment for Rev function in these CNS-based cells. Thus, these data suggest a molecular mechanism(s) for restricted replication in astrocytes as a potential low-level site of residual HIV-1 in vivo.

Astrocytes↗
PubMed2001

Nitric oxide and mechanisms of redox signalling: matrix and matrix-metabolizing enzymes as prime nitric oxide targets.

One of the greatest biomedical breakthroughs of the twentieth century was the discovery of endothelium-derived relaxing factor and its identification as nitric oxide (NO). NO has received special attention ever since: besides its potent vasodilatory and vasoprotective effects, NO was identified as a key player in innate immunity and was found to act as an unconventional type of neurotransmitter. This article focuses on mechanisms of NO signalling that form the basis of functional cell responses to accommodate changes in the cellular microenvironment. Redox-based regulation of signal transduction and, on a more long-term scale, changes in gene expression will be exemplified by NO-modulation of matrix components and matrix-metabolizing enzymes. It seems to be a safe bet that ongoing analyses of NO signalling and gene expression will provide a wealth of promising therapeutic targets in human diseases.

Animals↗
PubMed2003

Gene expression patterns in AIDS versus non-AIDS-related diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is more prevalent and more often fatal in AIDS patients compared to immune-competent individuals. Potential explanations for these differences include distinct tumorigenic mechanisms and/or altered cellular microenvironments. We previously discovered that the TCL1 (T-cell leukemia-1) proto-oncogene is expressed in a high proportion of AIDS-DLBCL compared to DLBCL cases and that aberrant TCL1 expression causes DLBCL in a new transgenic mouse model. Here, we continue to search for other genes that may contribute to the differential pathogenesis of DLBCL in AIDS. Gene subtraction yielded over 1800 potential AIDS-DLBCL candidates, of which about 50% were unknown and not further considered. The remaining 50% of genes were annotated and, when combined with miniarray screening from multiple patient samples, were reduced to 18 candidate genes for extended analysis. These 18 genes showed distinct patterns of expression in both AIDS-DLBCL and DLBCL samples. However, unlike TCL1, none of these genes was preferentially associated with either AIDS-DLBCL or DLBCL. Our data suggest that the increased incidence and severity of AIDS-DLBCL compared to DLBCL is likely due to crippled immune surveillance rather than to markedly different gene expression profiles.

DNA, Complementary↗
PubMed2003

NFkappaB inhibition decreases hepatocyte proliferation but does not alter apoptosis in obstructive jaundice.

INTRODUCTION: Cholestasis activates nuclear factor kappa B (NFkappaB), which is involved in both hepatocyte proliferation and apoptosis, depending on the cellular microenvironment. We hypothesized that NFkappaB inhibition would decrease hepatocyte proliferation and potentiate hepatocyte apoptosis in a rat model of extrahepatic biliary obstruction. AIM: To determine if NFkappaB inhibition concomitantly decreases hepatocyte proliferation and increases apoptosis in obstructive jaundice. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent either sham operation or bile-duct ligation (BDL) combined with portal vein injection of vehicle or 6 x 10(9) particles of an adenovirus carrying either the control luciferase or the IkappaB super-repressor (AdIkappaBSR) transgenes. Liver was harvested 3, 5, and 7 days after sham operation or BDL, and immunohistochemistry for proliferating cell nuclear antigen and terminal dUTP nick end-labeling was performed for detection of DNA synthesis and apoptosis, respectively. RESULTS: Increased serum total bilirubin and hematoxylin and eosin-stained liver sections confirmed cholestasis in BDL animals. Western blot analysis demonstrated IkappaBSR protein expression in AdIkappaBSR-infected animals only. At day 7, NFkappaB inhibition decreased hepatocyte DNA synthesis in BDL rats compared to both adenovirus carrying the control luciferase and vehicle-treated controls. Apoptosis was increased in BDL vehicle-treated animals compared to sham-operation animals, but NFkappaB inhibition did not alter hepatocyte apoptosis in the BDL group. CONCLUSION: In obstructive cholestasis, NFkappaB is required for hepatocyte proliferation, but does not augment apoptosis.

Adenoviridae↗
PubMed2002

Detection of reactive oxygen and nitrogen species in tissues using redox-sensitive fluorescent probes.

The take-home message of this chapter is that the fluorescent probes for ROS and RNS have great potential in improving our understanding of redox behavior within cells and tissues. However, data obtained from studies using these probes must be expressed in the context of the limitations of the chemistry of the probes in the cellular microenvironment, which may change under different conditions, such as cell stress or injury. In most cases, as suggested, results should be described in a general context of reflecting an increase in oxidizing reactions within the cell and not as a quantitative measure of the production of a specific oxidant species. It is highly recommended that results be verified, when possible, with alternative fluorescent probes or preferably using alternative methods, such as electron spin resonance or other newly emerging technology.

Animals↗
PubMed2003

cDNA microarray analysis reveals an overexpression of the dual-specificity MAPK phosphatase PYST2 in acute leukemia.

The information contained in the draft sequence of the human genome offers a solid basis to study gene function. The DNA microarray technology is one of the most important tools enabling the performance of such studies. The global expression analysis using microarrays enables the construction of a simultaneous expression pattern of thousands of genes and thus an unprecedented opportunity to obtain molecular signatures of the state of activity of diseased cells. Microarray analysis may thus provide invaluable information on disease pathology, progression, resistance to treatment, and response to cellular microenvironments. Ultimately such analyses may lead to improved early diagnosis and innovative therapeutic approaches. Yet, by employing this advanced technology in order to identify new target molecules for diagnosis or therapy, one is faced with the necessity to focUs on one or several genes and to investigate them further. A huge number of differentially expressed genes are usually identified when 2 cell samples are comparatively analyzed in an individual assay. Several factors, mainly a possible genetic diversity between the samples, minimize the capability of reaching an educated conclusion as to which gene or genes to select for further studies. Gene expression arrays were employed to identify genes whose expression characterizes leukemic leukocytes. Many different genes were differentially expressed by "leukemic-phase leukocytes," derived from three untreated acute myelogenous leukemia (AML) patients and by "remission-phase leukocytes," obtained from the same patients following induction of remission. However, only two of these genes, the dual-specificity MAPK phosphatase PYST2 and the tryptophan 5-hydroxylase, were found to be more highly expressed by the leukemic-phase than by remission-phase leukocytes of all three patients. The microarray results of only the PYST2 gene could be verified by RT-PCR. By focusing on genes that had a similar expression pattern in cells from multiple donors we overcame the problem of genetic diversity and identified, out of 60 differentially expressed genes, a single candidate target gene in AML. Pooling specimens in order to overcome the problem of genetic diversity (e.g., clinical material obtained from treated patients and from untreated ones), is not recommended because it may dilute the treatment effects. Therefore, it is essential to perform each experiment using individual preparations.

Adult↗
PubMed1998

Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors.

Extensive behavioral and biochemical evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacological properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor density and cellular microenvironment, we also examined the properties of DMT in native preparations using a behavioral and biochemical approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacological studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT. Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native preparation. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT.

3T3 Cells↗
PubMed1998

NMR studies of intra- and extracellular red blood cell lithium by transverse relaxation measurements and shift reagents.

Lithium salts are used in the treatment and prophylaxis of bipolar or mood disorders. The mechanism of action by which the cation exerts its therapeutic influence is unknown. A knowledge of brain Li concentration, its distribution in the brain, and its properties in the cellular microenvironment may have a strong influence on the understanding of Li function. The differentiation of lithium in the intra and extracellular environments has been achieved in a noninvasive manner in red blood cell (RBC) model. The two distinct transverse relaxation (T2) components have been observed in the blood sample drawn from lithium treated rats. These results indicate two different environments for Li with a fast (T2f) and a slow (T2s) component in the RBC model corresponding fractions that contribute to each relaxation component. The results compare well with the intra- and extracellular RBC lithium measured using shift reagents. Our studies indicate that the T2 method has utility in estimating the intracellular Li in systems that exhibit similar T2 behavior. The studies performed at different Li doses in the rat model indicate that the method may have utility in following a wide range of intracellular Li.

Animals↗
PubMed2000

[Osteoblastic regulation of osteoclast survival: effect of calcitriol].

Throughout life, bone is remodelled in a dynamic process which results in a balance between bone formation by osteoblasts and bone resorption by osteoclasts. It is now clearly established that osteoblasts/stromal cells are crucial for differentiation of osteoclasts, through a mechanism involving cell-to-cell contact. However, the possible involvement of osteoblasts and stromal cells in the survival of osteoclasts has not yet been clearly demonstrated. In this study, we assessed the influence of cellular microenvironment, especially osteoblasts, on the osteoclast survival. Our results have shown significant differences in osteoclastic survival between unfractionated bone cells and pure osteoclasts. Furthermore, we have shown that addition of 1.25(OH)2D3 to unfractionated bone cells resulted in a dose-dependent increase in osteoclast survival. Finally, we have shown that a conditioned medium obtained from rat osteoblastic cells cultured with calcitriol was able to increase significantly survival of pure osteoclasts. Taken together, these results strongly suggest that osteoblastic cells present in the bone microenvironment might play a role in the osteoclastic survival by producing soluble factor which modulate osteoclast apoptosis.

Animals↗
PubMed1997

Interleukin-10: biology, role in inflammation and autoimmunity.

LEARNING OBJECTIVES: Reading this article will increase the readers' knowledge of the biology of interleukin-10 (IL-10) an important cytokine. The survival of an organism and its host defense mechanisms require, among other processes, a complex but target-oriented interaction and an interdependence between the immune and inflammatory pathways. The biologic role of interleukin-10 in these processes is presented as well as the possible involvement of IL-10 in the pathogenesis of various diseases. The influence of pharmacologic agents on IL-10 production and the possible pharmacologic role of IL-10 itself are discussed. DATA SOURCES: A detailed literature search was conducted. Studies considered relevant and important involving both humans and animals, in all languages were used. STUDY SELECTION: Material was taken only from peer reviewed journals. RESULTS: IL-10 is produced by CD4+, Tho, Th1, B lymphocytes, mast cells, eosinophils, monocytes, macrophages and keratinocytes. IL-10 has a diverse array of actions, which differ depending on cell type, nature of stimulus and the cellular microenvironment. Interleukin-10 has an important role in the inflammatory and immune systems. In addition, present studies suggest that IL-10 may well play a pivotal role in the pathogenesis of several diseases. It has the potential for therapeutic use. Most of the data on IL-10 have been obtained from in vitro studies or animal experiments. Studies on humans are few, but rapidly increasing. CONCLUSIONS: Interleukin-10 is an important molecule with a central role in maintaining health and in the pathogenesis of disease. Known pharmacologic agents and some under investigation can modify IL-10 production in vivo. Development of agents that can selectively affect a very specific biologic action of IL-10 may provide significant benefit in treating autoimmune and inflammatory diseases.

Animals↗
PubMed2002

Improving the next generation of bioartificial liver devices.

Several extracorporeal bioartificial liver (BAL) devices are currently being evaluated as an alternative or adjunct therapy for liver disease. While these hybrid systems show promise, in order to become a clinical reality, BAL devices must clearly demonstrate efficacy in improving patient outcomes. Here, we present aspects of BAL devices that could benefit from fundamental advances in cell and developmental biology. In particular, we examine the development of human hepatocyte cell lines, strategies to stabilize the hepatocyte phenotype in vitro, and emphasize the importance of the cellular microenvironment in bioreactor design. Consideration of these key components of BAL systems will greatly improve next generation devices.

Animals↗
PubMed1999

Gene expression in individual cells: analysis using global single cell reverse transcription polymerase chain reaction (GSC RT-PCR).

The determination of the gene expression pattern of single cells has important implications for many areas of cellular and developmental biology including lineage determination, identification of primitive stem cells and temporal gene expression patterns induced by changes in the cellular microenvironment. Global Single Cell Reverse Transcription-Polymerase Chain Reaction (GSC RT-PCR) enables the study of single cell gene expression patterns. Initial observations of significant heterogeneity among single cells derived from a population of cells prompted us to determine how much of this observed heterogeneity was due to the intrinsic variation within the method. In this paper we discuss the sensitivity of GSC RT-PCR for analysis of differences in gene expression between single cells and, in particular, detail the amount of variation generated by the method itself. We found that most of the intrinsic variation in the method occurred in the PCR step. The total variation induced by the method was in the range of 5 fold. While we have determined that there is a five fold methodological variation in GSC RT-PCR, any method which use its components (including generation of cDNAs for microarray analysis) is likely to be affected by such experimental variability, which could limit the interpretation of the resulting data.

Analysis of Variance↗
PubMedDate not supplied

A novel full-scale flat membrane bioreactor utilizing porcine hepatocytes: cell viability and tissue-specific functions.

When designing an extracorporeal hybrid liver support device, special attention should be paid to providing the architectural basis for reconstructing a proper cellular microenvironment that ensures highest and prolonged functional activity of the liver cells. The common goal is to achieve high cell density culture and to design the bioreactor for full-scale primary liver cell cultures under adequate mass transfer conditions. An important aim of this study was to evaluate the biochemical performance of a flat membrane bioreactor that permits high-density hepatocyte culture and simultaneously to culture cells under sufficient oxygenation availability conditions comparable to the in vivo-like microenvironment. In such a bioreactor pig liver cells were cultured within an extracellular matrix between oxygen-permeable flat-sheet membranes. In this investigation we used a novel scaled-up prototype consisting of up to 20 modules in a parallel mode. Each module was seeded with 2 x 10(8) cells. Microscopic examination of the hepatocytes revealed morphological characteristics as found in vivo. Cell concentration increased in the first days of culture, as indicated by DNA measurements. The performance of the bioreactor was monitored for 18 days in terms of albumin synthesis, urea synthesis, ammonia elimination, and diazepam metabolism. The ability of the hepatocytes to synthesize albumin and urea increased during the first days of culture. Higher rates of albumin synthesis were obtained at day 9 and remained at a value of 1.41 pg/h/cell until day 18 of culture. The rate of urea synthesis increased from 23 ng/h/cell to 28 ng/h/cell and then remained constant. Cells eliminated ammonia at a rate of about 56 pg/h/cell, which was constant over the experimental period. Hepatocytes in the bioreactor metabolized diazepam and generated three different metabolites: nordiazepam, temazepam, and oxazepam. The production of such metabolites was sustained until 18 days of culture. These results demonstrated that the scale-up of the bioreactor was assessed, and it could be demonstrated that the device design aimed at the reconstruction of the liver-specific tissue architecture supported the expression of liver-specific functions of primary pig liver cells.

Albumins↗
PubMedDate not supplied

[The changes in the sphingenine/sphinganine ratio in sphingolipids of transplantable rat tumors depends on a transplantation organ].

The content of sphingenine (sphingosine) and sphinganine was determined in the total pool of sphingomyelin and ceramide in the rat tumors transplanted subcutaneously and intrahepatically. The sphingenine/sphinganine ratio in the subcutaneously transplanted sarcoma M1 and cholangiocellular carcinoma RS1 was lower than that in the sphingolipids of the intrahepatically transplanted tumors. However, the sphingenine/sphinganine ratio in the subcutaneously transplanted rat hepatoma 27 was higher than in the intrahepatically transplanted hepatoma. These observations indicate that the sphingenine/sphinganine ratio in sphingolipids of tumors depends on the tumor type and its cellular microenvironment.

Animals↗
PubMed1980

Friend leukaemia virus-transformed cells, unlike normal stem cells, form spleen colonies in Sl/sld mice.

Neoplastic cells are characterized by partial or total autonomy from the interactions that regulate the behaviour of normal cells in the intact animal. Despite the role of the host cellular environment in governing the proliferation and differentiation of both normal and malignant cells, little is known about these host factors. The characterization of host genes that influence both normal cellular processes, as well as susceptibility to tumour induction, is one approach to identifying such factors. Mice carrying two recessive mutations at the steel (Sl) locus have an environmental defect that affects both normal haematopoietic stem cell function as well as susceptibility to Friend leukaemia virus. In this study, we have used Sl/sld mice to examine whether malignant transformation by this RNA tumour virus results in a population of cells capable of proliferating even in the defective cellular microenvironment of Sl/sld mice. We report here that late after infection, the leukaemic spleens of Friend virus-infected mice contain cells which, unlike normal haematopoietic stem cells, are able to form macroscopic spleen colonies in irradiated mice of genotype Sl/Sld. This observation forms the basis for the first in vivo colony assay for leukaemic cells transformed by Friend virus.

Animals↗