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PubMed2006

HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth.

The division, differentiation, and function of stem cells and multipotent progenitors are influenced by complex signals in the microenvironment, including oxygen availability. Using a genetic "knock-in" strategy, we demonstrate that targeted replacement of the oxygen-regulated transcription factor HIF-1alpha with HIF-2alpha results in expanded expression of HIF-2alpha-specific target genes including Oct-4, a transcription factor essential for maintaining stem cell pluripotency. We show that HIF-2alpha, but not HIF-1alpha, binds to the Oct-4 promoter and induces Oct-4 expression and transcriptional activity, thereby contributing to impaired development in homozygous Hif-2alpha KI/KI embryos, defective hematopoietic stem cell differentiation in embryoid bodies, and large embryonic stem cell (ES)-derived tumors characterized by altered cellular differentiation. Furthermore, loss of HIF-2alpha severely reduces the number of embryonic primordial germ cells, which require Oct-4 expression for survival and/or maintenance. These results identify Oct-4 as a HIF-2alpha-specific target gene and indicate that HIF-2alpha can regulate stem cell function and/or differentiation through activation of Oct-4, which in turn contributes to HIF-2alpha's tumor promoting activity.

Alleles↗
PubMed1988

Dry deposition of airborne sulfate and nitrate to soybeans.

Dry deposition contributes a substantial part of the total deposition of acidic pollutants and acid precursors to agricultural systems. However, because of the relative intractability of measurement of dry deposition fluxes, little work has been done to directly quantify dry inputs of pollutants to crops. In this research, foliar surface sampling ('leaf-washing') methods were developed and shown to be a practical and fairly precise means of monitoring the accumulation of dry-deposited SO4(2-) and NO3- on plant surfaces. Leaching of these ions from plant tissues was shown to be negligible; however, uptake by plants (e.g. stomatal gas exchange of SO2 or HNO3 and/or assimilation of surface accumulations of materials) is not accounted for by the sampling method. The significance of dry deposition to modification of the chemical microenvironment of leaf surfaces appears to be a factor of 3 to 20 or more greater than that of wet deposition alone. This is due to the cyclic reactivation of accumulated materials by dew and light rains, which may dissolve and mobilize, but not remove, the pollutant surface deposit. Therefore, while dry deposition of SO2 and SO4(2-) containing particles may contribute only part of the total mass of sulfur inputs to crop systems, the exposure of plant surface tissue to pollutants can be dominated by the dry-deposited material. The alteration of leaf surface chemistry may contribute to possible stress-producing mechanisms such as reduction of cuticular integrity, cellular injury and death, enhanced leaching of primary and secondary metabolites, and changes in pathogen infection efficiency.

Journal Article↗
PubMed2005

Vessel maturation effects on tumour growth: validation of a computer model in implanted human ovarian carcinoma spheroids.

We analysed measurements of tumour growth, neovascular maturation and function in human epithelial ovarian carcinoma xenografts, studied noninvasively by magnetic resonance imaging. Results suggest that vascular maturation and mature and immature vessel regression occur continuously during tumour neovascularisation. Moreover, in these spheroids, a high tumour growth-rate is associated with monotonic changes in vessel density (VD) and with large proportions of mature blood vessels, whereas a lower tumour growth-rate is associated with fluctuating VD and lower proportions of mature vessels. These results corroborate a mathematical model for tumour dynamics, including vascular maturation and immature and mature vessel regression. The model predicts that rapid tumour growth may result from a high maturation-rate of neo-vasculatures, due to substantial mature VD in the microenvironment, while a slower tumour growth is an outcome of a lower background VD, leading to a lower vessel maturation-rate, larger proportion of immature vessels and, consequently, to regression-driven instabilities. The generality of these results for other tumour types should be validated.

Animals↗
PubMed2005

Role of B7-H1 and B7-H4 molecules in down-regulating effector phase of T-cell immunity: novel cancer escaping mechanisms.

The majority of human and rodent cancers display various antigens which could elicit cellular and humoral immune responses. Such immunity, however, often fails to prevent progressive growth of cancers. It has long been speculated that tumor antigens may not be presented in appropriate fashion, which subsequently fails to elicit a strong immune response. Recent studies, however, indicate that immunization by formulated tumor antigens or even transfer of pre-activated T lymphocytes also have limited impact on cancer growth despite the fact that these methods could often enhance immune responses in cancer patients. These findings imply that even afferent arm of immunity are strengthen, it is not necessarily being translated to tumor regression. It is possible that the development of evasion mechanisms in tumor microenvironment play a critical role in the resistance of therapeutic immune responses. Recent studies provide compelling evidence that human and rodent cancers develop evasion mechanisms by aberrantly expressing normal proteins, which are required for normal tissue homeostasis, to either build a microenvironment locally or reach other organs systemically. In this review, we will focus our discussion on two recently described molecules, B7-H1 and B7-H4, in the context of their roles in the evasion of tumor immunity and possible approaches for therapeutic manipulation.

Antigens, CD↗
PubMed2002

Autocrine/paracrine involvement of parathyroid hormone-related peptide in vascular leiomyoma.

Vascular leiomyomas are believed to arise from the smooth muscle of blood vessels and are characterized by the proliferation of vascular smooth muscle cells (VSMC) and numerous slit-like vascular lumens. Parathyroid hormone (PTH)-related peptide (PTHrP) plays an important role in local autocrine and/or paracrine regulation of cellular growth and function in VSMC. To investigate the interaction between VSMC and endothelial cells, we evaluated the distribution of PTHrP and PTH/PTHrP-receptor in 10 vascular leiomyomas of the skin by immunohistochemistry and in situ hybridization (ISH) of paraffin-embedded specimens. Both immunohistochemistry and ISH revealed that PTH/PTHrP-receptors are expressed in endothelial cells lining areas with slit-like vascular lumens and very weakly expressed in proliferating VSMC in all vascular leiomyomas. On the other hand, PTHrP itself was localized mainly in proliferating VSMC. These results support the hypothesis that PTHrP acts through the PTH/PTHrP-receptor via an autocrine and/or paracrine mechanism from VSMC to endothelial cells in the formation of characteristic microenvironments of vascular leiomyoma cell composition.

Adult↗
PubMed2004

Activation of signaling lymphocytic activation molecule triggers a signaling cascade that enhances Th1 responses in human intracellular infection.

T cell production of IFN-gamma contributes to host defense against infection by intracellular pathogens, including mycobacteria. Lepromatous leprosy, the disseminated form of infection caused by Mycobacterium leprae, is characterized by loss of cellular response against the pathogen and diminished Th1 cytokine production. Relieving bacterial burden in Ag-unresponsive patients might be achieved through alternative receptors that stimulate IFN-gamma production. We have previously shown that ligation of signaling lymphocytic activation molecule (SLAM) enhances IFN-gamma in mycobacterial infection; therefore, we investigated molecular pathways leading from SLAM activation to IFN-gamma production in human leprosy. The expression of the SLAM-associated protein (an inhibitory factor for IFN-gamma induction) on M. leprae-stimulated cells from leprosy patients was inversely correlated to IFN-gamma production. However, SLAM ligation or exposure of cells from lepromatous patients to a proinflammatory microenvironment down-regulated SLAM-associated protein expression. Moreover, SLAM activation induced a sequence of signaling proteins, including activation of the NF-kappaB complex, phosphorylation of Stat1, and induction of T-bet expression, resulting in the promotion of IFN-gamma production, a pathway that remains quiescent in response to Ag in lepromatous patients. Therefore, our findings reveal a cascade of molecular events during signaling through SLAM in leprosy that cooperate to induce IFN-gamma production and strongly suggest that SLAM might be a focal point for therapeutic modulation of T cell cytokine responses in diseases characterized by dysfunctional Th2 responses.

Adjuvants, Immunologic↗
PubMed1991

Oxygen regulated 80 kDa protein and glucose regulated 78kDa protein are identical.

Ischemic stress of cells within solid tumors arises from inadequate perfusion of regions of the tumor and results in microenvironments which are hypoxic and deficient in nutrient delivery and waste product removal. Stressed cells within these microenvironments show growth inhibition and synthesize unique sets of proteins referred to as glucose and oxygen regulated proteins (GRPs and ORPs respectively). The commonality of proteins induced by glucose-starvation and hypoxia has not been proven. To this end, ORPs were induced in Chinese hamster ovary cells in the presence of high glucose concentration in the media and ORP 80 isolated from two dimension gels. Eleven tryptic peptides of the 80 kDa ORP were sequenced and found to be identical to GRP 78 sequences. The data demonstrate that GRP 78 and ORP 80 have the same primary amino acid sequence and suggest that glucose-starvation and hypoxia can induce the same cellular responses.

Amino Acid Sequence↗
PubMed2005

Repair of impaired myocardium by means of implantation of engineered autologous myoblast sheets.

OBJECTIVES: Autologous skeletal myoblast cell transplantation by means of the injection method is subject to the loss of intercellular communication, extracellular matrix, and cell numbers. We hypothesize that the implantation of skeletal myoblast cell sheets might be more advantageous in repairing the impaired heart by providing uniform and stable cell delivery with less cell loss and without disrupting the cell-cell microenvironment. METHODS: Left anterior descending coronary artery-ligated Lewis rat hearts (2 weeks, total n = 173) received 1 x 10(7) autologous skeletal myoblasts by means of cell transplantation either through myoblast injection or implantation of 2 monolayer-constructed myoblast sheets (5 x 10(6) cells per sheet) or through medium injection. Myoblast sheets were constructed with temperature-responsive, polymer-grafted cell-culture dishes, which release the confluent cells from the dish surface at less than 20 degrees C. RESULTS: Echocardiographic results indicated higher improvement of cardiac performance in the myoblast sheet group than among the other groups until 8 weeks after cell transplantation. Histologic comparison revealed greater cellularity and abundant widespread neocapillaries within the noticeable uniform thickened wall in myoblast sheet group hearts only. Fibrosis was substantially reduced with skeletal myoblast sheet implantation compared with skeletal myoblast cell injection. Obviously higher numbers of hematopoietic stem cells (c-kit, stem cell antigen 1, and CD34) were observed in the myoblast sheet group infarct heart region. Reverse transcription-polymerase chain reaction results showed expression of stromal-derived factor 1, hepatocyte growth factor, and vascular endothelial growth factor as follows: myoblast sheets > myoblast injection > control. CONCLUSIONS: Myoblast sheets repaired the impaired myocardium, reduced fibrosis, and prevented remodeling in association with recruitment of hematopoietic stem cells through the release of stromal-derived factor 1 and other growth factors. Our experiment indicates a therapy for patients with severe heart failure.

Animals↗
PubMed2003

How not to get bugged by bugs: mechanisms of cellular tolerance to microorganisms.

PURPOSE OF REVIEW: Advances in the characterization of the receptors and signaling pathways involved in the response to infection have led to a more detailed understanding of cellular tolerance to endotoxin and other microbial components. This review summarizes recent progress in the field, particularly in relation to the molecular mechanisms that underlie the development of tolerance to microorganisms. RECENT FINDINGS: The identification of Toll-like receptors as major sensors of microbial molecules has led to numerous studies of their function in tolerant cells. Decreased Toll-like receptor expression, altered interactions between the Toll-like receptors and intracellular signal transducers, and decreased expression or activity of downstream signaling molecules have all been implicated. Upregulation of specific proteins that inhibit Toll-like receptor signaling has also been described. Apart from these general mechanisms, special features of the intestinal microenvironment and its resident cells also contribute to making the gut hyporesponsive to microorganisms. SUMMARY: The application of gene knockout technology has highlighted the importance of macrophage tolerance in regulating innate immunity to microbial infection. Such studies have indicated that the failure of tolerance can lead to exaggerated inflammatory responses to intestinal bacteria, raising the possibility that defects in tolerance may be linked to conditions such as inflammatory bowel disease. Further characterization of this link will help in elucidating the pathogenesis of such conditions and in devising new approaches to treatment.

Journal Article↗
PubMed2001

Biological consequences of tumor hypoxia.

Growing evidence from experimental and clinical studies points to the fundamental, pathophysiologic role of hypoxia in solid tumors. Intratumoral hypoxia is a consequence of a structurally and functionally disturbed microcirculation, with deterioration of the diffusion geometry and of tumor-associated anemia. Hypoxia-induced changes of the proteome in the neoplastic and stroma cells may lead to neoplastic growth impairment through molecular mechanisms, resulting in cellular quiescence, differentiation, and apoptosis. Alternatively, hypoxia-induced proteome changes activating nonspecific stress response, anaerobic metabolism, angiogenesis, tissue remodeling, and change of cell contacts may promote tumor propagation by enabling neoplastic cells to overcome the nutritive deprivation through adaptation or escape from the "hostile" environment. Whether the phenotypic result of hypoxia-induced proteome change is impairment, stasis, or promotion of neoplastic growth is thought to be determined by the genome of the tumor cells and additional microenvironmental factors. Tumor cells with genomic alterations (such as loss of apoptotic potential) allowing their survival under hypoxia will aggravate tumor hypoxia. Sustained hypoxia increases genomic instability, genomic heterogeneity, and the selection pressure of the microenvironment. New variants even better adapted to survive and proliferate under reduced pO2 will be selected through clonal expansion. These variants will further drive the vicious circle of malignant progression which is clinically characterized by an increasing probability of local, perifocal, regional, and distant spread.

Animals↗
PubMed1991

Theoretical considerations on cell ensembles.

Structure-function interdependency must apply at the supracellular level as well as at cellular and molecular levels. The overall structure and the intercellular geometry of the multicellular erythroblastic island, although strongly dependent upon molecular interactions (which determine or modulate recognition, adhesion, and the like), also carry consequences at a more general physical-chemical level. These relate to such factors as local concentrations and gradients, the nature of the forces and the phase-state of the material in the intercellular region, the generalized intercellular transport processes (diffusional, osmotic, electrokinetic, hydrodynamic, etc.), and the dynamic coupling of flows. Such "other-level" phenomena must play a significant role, and therefore must be taken into account, in formulating a comprehensive picture of the ways in which the microenvironment acts in the management and control of the processes of hematopoietic differentiation and development.

Animals↗
PubMed1982

Combinatorial process for extracellular matrix influences on gene expression: a hypothesis.

The extracellular matrix (ECM) has a number of influences on gene expression during growth and development. Cellular and tissue interactions among similar and dissimilar cell types result in the production of complex and fascinating extracellular matrices throughout development. This paper presents a hypothesis that will emphasize those examples in which the extracellular matrix mediates de novo gene expression termed "determination" of a unique phenotype. It will be found that a number of gene families within the eucaryotic genome can be preferentially activated during the course of differentiation-specific protein expression. Results from a number of laboratories illustrate that close-range and/or short-range cell-cell interactions invoke preferential differentiation-specific protein synthesis and accumulation during embryogenesis. This discussion will highlight how the extracellular matrix microenvironment of a particular population of cells invokes irreversible, differentiation-specific gene expression. Recent advances in the isolation and characterization of a large number of different extracellular matrix macromolecules (eg various types of collagens, fibronectin, chondronectin, osteonectin, laminin, proteoglycans, enamel protein) now suggest a renewed interest in this problem area, and also the promise for significant breakthroughs in the near future. The combinatorial hypothesis for extracellular matrix influences on gene expression states that changing, rearranging, or altering the macromolecular constituents within ECM results in a myriad diversity in developmental instructions. The hypothesis predicts that no individual morphogen is required.

Cell Communication↗
PubMed1996

Coelom-associated lymphomyeloid tissue (milky spots): site of lymphoid and myelomonocytic cell generation.

Pleural and peritoneal milky spots (MS) are small morphofunctional structures representing subsidiary foci of coelom-associated lymphomyeloid tissue (CALT). In this paper we studied the cellular composition of CALT in normal and Schistosoma mansoni-infected mice. In the healthy mouse, CALT is mainly composed of IgM (+) B cells and presents lower numbers of CD23 and CD45R (B220) B2 lymphocytes. When activated by the infection, it may show pronounced lymphocytosis, plasmocytogenesis (IgM > IgG > IgA > IgG2a > IgG1) and myelomonocytosis. The lymphocytes were mainly of the B1 type (double positive CD5/IgM), with smaller number of T cells (TCR alpha beta (+), TCR gamma delta (+), CD3 (+) and CD5 (+)) and conventional B2 cells (B220 (+), CD23 (+)). The myeloid compartment was composed of immature and mature cells of monocyte/macrophage, eosinophil, neutrophil and megakaryocytic lineages, especially in the omental milky spots. CALT is also a favorable microenvironment for LFA-1 (+) mast cells. Thus, CALT appears to be a mixed lymphoid organ, with secondary and/or primary lymphoid organ functions, being an important site of B1 cell generation, plasma cell maturation and extramedullar hematopoiesis. CALT operates as an interface between blood and lymphatic circulation and coelomic cavities, because locally or externally produced cells have easy and ready access to the pleural and peritoneal cavities. Furthermore, MS cells can escape into blood and lymphatic vessels, providing lymphocytes to other lymphoid organs and to the mucosa-associated lymphoid tissue.

Animals↗
PubMed2006

Does the tumor microenvironment influence radiation-induced apoptosis?

UNLABELLED: Cytotoxic anti-cancer agents induce apoptosis in tumor and normal tissues. Therefore, it is important to investigate which factors determine these apoptotic processes and hence their likely impact on therapeutic gain. Radiation-induced apoptosis in tumors may be inhibited due to mutations of apoptotic elements or to tumor microenvironmental conditions arising from vascular insufficiency. Tumors typically contain regions of hypoxia, low glucose and acidosis. Hypoxic cells compromise treatment partly because of reduced fixation of damage during radiotherapy and partly because they promote a more malignant phenotype. There is also evidence that hypoxia may inhibit apoptosis. For some cell types, concurrent hypoxia may modulate radiation-induced apoptosis while, for others, post-irradiation hypoxia may be required. This may reflect the activity of different apoptotic pathways. Pathways involving mitochondrial components as well as regulation of SAPK and Fas have been implicated. In addition, several key stages in apoptosis are sensitive to depletion of cellular energy reserves, which results from hypoxia and low glucose conditions. There is also evidence that low pH in tumors can interfere with radiation-induced apoptosis, partly through cell cycle arrest and other undefined mechanisms. CONCLUSIONS: Hypoxia, low glucose and acidosis influence radiation-induced apoptosis and thus may be detrimental to radiotherapy.

Animals↗
PubMed2006

Axon initial segment ensheathed by extracellular matrix in perineuronal nets.

Perineuronal nets of extracellular matrix are associated with distinct types of neurons in the cerebral cortex and many subcortical regions. Large complexes of aggregating proteoglycans form a chemically specified microenvironment around the somata, proximal dendrites and the axon initial segment, including the presynaptic boutons attached to these domains. The subcellular distribution and the temporal course of postnatal formation suggest that perineuronal nets may be involved in the regulation of synaptic plasticity. Here we investigate structural and cytochemical characteristics of the extracellular matrix around axon initial segments virtually devoid of synaptic contacts. Wisteria floribunda agglutinin staining, the immunocytochemical detection of aggrecan and tenascin-R, as well as affinity-labeling of hyaluronan were used to analyze perineuronal nets associated with large motoneurons in the mouse superior colliculus. The molecular composition of perineuronal nets was divergent between neurons but was identical around the different cellular domains of the individual neurons. The axon initial segments largely devoid of synapses were covered by a continuous matrix sheath infiltrating the adjacent neuropil. The periaxonal zone penetrated by matrix components often increased in diameter along the initial segment from the axon hillock toward the myelinated part of the axon. The axonal and somatodendritic domains of perineuronal nets were concomitantly formed during the first three weeks of postnatal development. The common molecular properties and major structural features of subcellular perineuronal net domains were retained in organotypic midbrain slice cultures. The results support the hypothesis that the aggrecan-related extracellular matrix of perineuronal nets provides a continuous micromilieu for different subcellular domains performing integration and generation of the electrical activity of neurons.

Animals↗
PubMed2026

SpatialRNA: a Python package for easy application of Graph Neural Network models on single-molecule spatial transcriptomics dataset.

SUMMARY: Image-based spatial transcriptomics (iST) deliver gene expression measurements of RNA transcripts in tissue slices with single-molecule resolution and spatial context preserved. Modern Graph Neural Network (GNN) models are promising methods for capturing the complex molecular and cellular phenotypes in tissues at single-transcript and single-cell levels. A key application of GNNs is the detection of spatial domains or niches, that is, groups of molecules and/or cells that collaboratively work together to produce complex phenotypes. Due to the vast number of detected transcripts in (iST) dataset, applying GNNs on RNA molecule graphs is not trivial. We present a Python package, SpatialRNA, for easy (sub)graph generation from tissue samples and provide comprehensive tutorials for convenient and efficient application of Graph Neural Network models under the PyG framework. This highly scalable tool comprehensively segments tissue into spatial domains, aiding in biological interpretation of iST data and its underlying molecular microenvironments. AVAILABILITY AND IMPLEMENTATION: The SpatialRNA package is freely accessible from online repository https://github.com/ruqianl/spatialrna and can be installed via pip. Comprehensive tutorials, guidance on parameter selection, and complete workflows of case studies are available from the documentation website https://ruqianl.github.io/spatialrna_docs/, and uploaded on Zenodo with a DOI 10.5281/zenodo.17339575.

Neural Networks, Computer↗
PubMed2026

A CFH- and SPINT2-based prognostic signature for cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant tumor with a poor prognosis, and reliable biomarkers for postoperative risk stratification remain limited. This study aimed to develop and validate a CFH- and SPINT2-based prognostic signature to support postoperative risk stratification and inform adjuvant therapy selection in CCA through integrative machine learning and single-cell transcriptomics. METHODS: Differentially expressed genes were screened from GSE26566. Integrative machine learning (least absolute shrinkage and selection operator-Cox, random forest, and univariate Cox regression) was performed in the training cohort (GSE89749; n=115) to construct a risk model, which was externally validated in two independent cohorts: cohort 1 (E-MTAB-6389; n=75) and cohort 2 [The Cancer Genome Atlas Cholangiocarcinoma (TCGA-CHOL) data set; n=36]. Systematic analysis was conducted and included examinations of immune infiltration [via single-sample gene set enrichment analysis (ssGSEA)], pathway enrichment (via hallmark GSEA), cellular localization (via single-cell RNA sequencing), and drug sensitivity (via the Genomics of Drug Sensitivity in Cancer 2 database). RESULTS: Two genes, CFH and SPINT2, were identified and incorporated into a prognostic risk score. High-risk patients in the training cohort had a significantly worse overall survival (log-rank P=0.02). External validation was performed in two independent cohorts. In validation cohort 1, the risk group was an independent prognostic factor [hazard ratio =2.27, 95% confidence interval (CI): 1.18-4.37; P=0.01]. In validation cohort 2, the model demonstrated acceptable discriminative ability (concordance index =0.721; 3-year area under the curve =0.692). The high-risk group exhibited an immunosuppressive microenvironment characterized by increased infiltration of macrophages and myeloid-derived suppressor cells, along with the activation of epithelial-mesenchymal transition, inflammatory response, and NF-κB signaling pathways. Single-cell analysis revealed a cell-type-specific expression pattern: CFH was predominantly expressed in fibroblasts, while SPINT2 was mainly expressed in malignant cells. Drug sensitivity analysis demonstrated that the high-risk group was more sensitive to gemcitabine, cisplatin, poly(ADP-ribose) polymerase (PARP) inhibitors, and mammalian target of rapamycin (mTOR) inhibitors, whereas the low-risk group was more sensitive to lapatinib. CONCLUSIONS: The CFH- and SPINT2-based prognostic signature may serve as an independent biomarker for postoperative risk stratification in CCA. High-risk patients, characterized by fibroblast-derived CFH enrichment and malignant-cell SPINT2 loss, exhibit an immunosuppressive microenvironment and may be more suitable for gemcitabine-based chemotherapy or PARP/mTOR inhibitors, whereas low-risk patients may benefit from less intensive adjuvant strategies or HER2/EGFR-targeted lapatinib. Prospective validation is warranted before clinical implementation.

Cholangiocarcinoma (CCA)↗
PubMed1997

[The action of epidermal growth factor on the development of cultured striatum cells].

INTRODUCTION: Epidermic growth factor (EGF) has a neurotrophic mitogenic effect on different cell populations in the nervous system. This is modulated by the stage of development and microenvironment of the cells. OBJECTIVE AND METHODS: In this paper we describe the action of EGF on embryonic striatum cells of a culture system dissociated from neurons and glias. The cell culture is prepared from 16-17 day rat embryos. In the system used, the cell population was cultured for 20-24 hours in a medium containing serum. This medium was later replaced by a mixture of specific nutrients and treated for 6 days with 20 mg/ml of EGF. RESULTS AND CONCLUSIONS: The substitution of serum during the initial period of development led to an appreciable reduction in the living cells in the treated cultures and in the controls. The surviving cells were mainly cellular precursors, taking into account their morphological characteristics and capacity for proliferation. The effect of EGF was seen in an increase in the number of cells and was shown to be a stimulus to the proliferation of neuronal and astrocyte precursors. The specific activity of choline acetyl-transferases determined in the cultures at 16 days showed differentiation of a cholinergic neurons subpopulation, which responded to treatment with nerve growth factor with an increase in the activity of this enzyme.

Animals↗