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Epidermal Growth Factor Promotes a Neural Phenotype in Thymic

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Epidermal Growth Factor Promotes a Neural Phenotype in Thymic Epithelial Cells and Enhances Neuropoietic Cytoldne Expression Isabella Screpanti,* Susanna Scarpa,* Daniela Meco,* Diana BeUavia,~ Liborio Stuppia, § Luigi Frati, *u Andrea Modesti,* and Alberto Gulino I *Department of Experimental Medicine and Pathology, University La Sapienza, 00161 Rome;qnstitute of Human Pathology and Social Medicine, University of Chieti, 66100 Chieti; §Institute of N.P. Human Cytomorphology, National Research Council, 66100 Chieti; and UMediterranean Institute of Neuroscience, Pozzilli and IDepartment of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy Abstract. Neural crest-derived cells populate the thy- growth factor enhances cells that express the genes en- Downloaded from http://rupress.org/jcb/article-pdf/130/1/183/1264385/183.pdf by guest on 29 September 2021 mus, and their coexistence with epithelial cells is re- coding the preprotachykinin A-generated neuropep- quired for proper organ development and T cell educa- tides and the bipotential neuropoietic and lymphopoi- tion function. We show here that epidermal growth etic cytokines ciliary neurotrophic factor and factor (EGF), a major epithelial cell growth-enhancing interleukin-6. These cytokines also enhance the neu- agent, has a morphogenetic action to promote the ex- ronal phenotype of thymic epithelial cells. Therefore, pression of a neuronal phenotype (e.g., neurofilament EGF appears to be a composite autocrine/paracrine expression) in cultured thymic epithelial cells that are neuromodulator in thymic stroma. This suggests that characterized by a cytokeratin-positive epithelial cell EGF may regulate thymus-dependent immune func- background. The proliferation of such neurodifferenti- tions by promoting neuronal gene expression in neural ated cells is also enhanced by EGF. Furthermore, the crest-derived cells. ULTIPLE cell interactions control developmental unclear, although the presence of neural crest-derived cells cell fate and morphogenesis. The morphoge- in thymic medulla and the expression of a number of neu- M netic process of the thymus is an example in ronal markers and neuropeptides in both thymic epithe- which the variety of phenotypes resulting from T lymphoid lium in vivo (14, 18, 20, 42) and thymic stromal cell cultures cell developmental pathways and the acquisition of either (50) have been described. Cytokeratin-harboring thymic the ability to react to external antigens or the tolerance nurse epithelial cells also express most of these neuron and against self-antigens arise through the action of instructive neuroendocrine markers and neuropeptides (19). and/or selective differentiation signals generated by the The coexistence of epithelial and neural cells within the thymic stroma in close association with precursor and dif- thymic stroma raises the question as to the nature of the ferentiating lymphoid cells (8, 47, 51). A striking aspect of regulatory signals that determine the development and the thymic stroma is the coexistence of cell types arising survival of the neuronal component. EGF is a likely candi- from distinct cell lineages represented mainly by the endo- date as a soluble regulatory signal. Indeed, in addition to derm of the third pharyngeal pouch, the ectoderm of the being a potent growth factor for several epithelial cell third branchial cleft and cells from the corresponding re- types (10), EGF and its receptor are expressed in the cen- gion of the neural crest (35, 36). The interaction of neuro- tral nervous system (CNS) 1 (15, 21) and the growth factor ectoderm-derived cells with other epithelial cells is neces- promotes both neuron survival and mitogenesis of neu- sary for both the organ morphogenic and the T cell ronal progenitors derived from neonatal rat retina and differentiation processes. Indeed, ablation of the cephalic adult mouse striatum (1, 41, 45, 59). Furthermore, EGF re- neural crest in chicken embryos results in thymic aplasia/ ceptor ligands (EGF and TGFet) are also expressed by hypoplasia (4, 7). The further fate and specific functions of thymic tissue in vivo and by human thymic epithelial cell neural crest-derived cells within the thymic stroma remain 1. Abbreviations used in this paper: BrdU, bromodeoxyuridine; CNTF, cil- iary neurotrophic factor; EGF, epidermal growth factor; IL-6, interleukin- Address all correspondence to Dr. Isabella Screpanti, Department of Ex- 6; NF, neurofilarnent; PPT-A, preprotachykinin-A; RT-PCR, reverse perimental Medicine and Pathology, University La Sapienza, viale Regina transcription-polymerase chain reaction; SYN, synapsin-1; TC, thymic Elena 324, 00161 Rome, Italy. Tel.: 39 6 44700816. Fax: 39 6 4454820. stromal cell; TH, tyrosine hydroxylase. © The Rockefeller University Press, 0021-9525/95/07/183/10 $2.00 The Journal of Cell Biology, Volume 130, Number 1, July 1995 183-192 183 cultures, in which these factors modulate the production of Mountain View, CA). Cell debris and doublets were excluded from analy- several cytokines (including interleukin-6 [IL-6]) (25, 32). sis by appropriate gating using physical parameters. The ability of EGF to enhance IL-6 production is of par- ticular interest. IL-6 belongs to the neuropoietic cytokine Immunofluorescence and Immunoperoxidase Staining family that influences the survival, proliferation, and dif- Immunofluorescence staining was performed using cells grown on slide ferentiation of neurons (12, 24). We have previously culture chambers, in the absence or presence of 10 ng/ml of EGF (Collab- shown that IL-6 is able to enhance the neural phenotype orative Res. Inc., Bedford, MA), 0.5 ng/ml recombinant murine IL-6 of thymic stromal cells (50). The aim of this work is there- (British Biotechnology, Oxford, UK), or 10 ng/ml recombinant rat ciliary neurotrophic factor (CNTF; Genzyme, Cambridge, MA). After washing fore to study the role of EGF in regulating the neural cell with PBS, cells were immediately fixed with ice-cold absolute ethanol for population in thymic stroma and the neurotrophic mi- 5 rain and incubated with various primary polyclonal or monoclonal anti- croenvironment sustained by these cells. bodies for 1 h at room temperature, washed with PBS, and then incu- bated with Fluorescein (FITC)-conjugated goat anti-rabbit or anti-mouse (Fab') IgG (Sigma) for 45 rain at room temperature. For EGF receptor Material and Methods staining, cells were preincubated for 2 h in medium without FCS and then fixed with 2% buffered paraformaldehyde for 10 min at room tempera- ture. Primary antibodies used included polyclonal rabbit anti-EGF and Thymic Stromal Cell Cultures anti-EGF receptor (Oncogene Science, Manhasset, NY), monoclonal anti- Several murine thymic stromal cell (TC) cultures were independently es- tyrosine hydroxylase (clone 2/40/15) and anti-neurofilaments (NF) 200 kD tablished from 4-5-wk-old C57BL/6 mice as previously described (38, 50). (clone NE14) (both from Boehringer Mannheim GmbH, Mannheim, Ger- Human thymic stromal cell (HTC) cultures were also independently es- many), anti-NF 160 kD (Amersham Corp., Buckingamshire, UK), pan- tablished from thymuses of children undergoing cardiac surgery. Cells cytokeratin monoclonal antibody (clone LU5, Boehringer Mannheim were cultured in RPMI 1640 medium supplemented with 10% FCS and GmbH), rabbit polyclonal anti-synapsin I antiserum (a gift from P. De Downloaded from http://rupress.org/jcb/article-pdf/130/1/183/1264385/183.pdf by guest on 29 September 2021 0.1 mg/ml sodium pyruvate and antibiotics (Hyclonc Europe Ltd., Cram- Camilli, Yale University School of Medicine, New Haven, CT), and mono- lington, UK). All experiments reported were performed with TC cultures clonal anti-CNTF (Boehringer). from the 3rd to 40th passage. Double-immunofluorescence staining was performed by labeling cells with anti-cytokeratin monoclonal antibody followed by fluorescein-conju- Flow Cytometry and Cell Cycle Analysis gated goat anti-mouse IgG and then with anti-NF 200 kD rabbit poly- clonal antibody (Sigma) followed by rhodamine-conjugated anti-rabbit Cell cycle analysis was performed by fixing 1 x 106 control or 48 h EGF- IgG (ICN ImmunoBiologicals, Lisle, IL). Fluorescent images were ana- treated cells in 70% cold ethanol for 30 min at 4°C and adding, after two lyzed with a fluorescence microscope (DMRB; Leitz, Wetzlar, Germany) washes in cold PBS, 0.5 mg/ml RNAse (Sigma Chemicals Co., St. Louis, or a confocal laser scanning microscope (TCS 4D; Leica, Inc., Deerfield, MO), and 40 Ixg/ml of propidium iodide (Sigma). Cells were then kept in IL). In the latter case, the green (FITC) and the red (rhodamine) fluores- the dark at 4°C for 30 min and immediately analyzed by flow cytometry. cences were independently recorded and elaborated through a 3-D func- The propidium iodide fluorescence emission, due to DNA content of indi- tion (Extended Focus or Shadow Forming Projection). The 3-D-obtained vidual cells, was filtered through a 585/42-nm band pass filter and mea- images were then independently observed or electromcally superimposed sured on a linear scale using a FACScan cytometer (Becton Dickinson, to simultaneously demonstrate the double staining. Figure 1. Expression of EGF and EGF receptor in TC-1S cells and thymic tissue. (A) Fluorescence photomicro- graph of cells immunoreactive for EGF. (B) RNA isolated from mouse submaxillary glands or thymus or TC-1S cells was processed for RT- PCR using either EGF or [3-actin primers as described. Results are shown as ethidium bromide staining
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