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1571.Full-Text.Pdf Epidermal Growth Factor Increases Undifferentiated Pancreatic Embryonic Cells In Vitro A Balance Between Proliferation and Differentiation Corentin Cras-Me´neur, Lynda Elghazi, Paul Czernichow, and Raphael Scharfmann During embryonic life, the development of a proper implicated in pancreatic development (1), the control of mass of mature pancreatic tissue is thought to require pancreatic cell growth and differentiation by growth fac- the proliferation of precursor cells, followed by their tors remains poorly understood. The goal of the present differentiation into endocrine or acinar cells. We inves- work was to determine whether by perturbing the prolif- tigated whether perturbing the proliferation of pre- eration of pancreatic precursor cells, the final mass of cursor cells in vitro could modify the final mass of endocrine cells that develop could be modified, with the endocrine tissue that develops. For that purpose, we objective of defining new strategies for increasing the final used activators or inhibitors of signals mediated by ␤-cell mass. receptor tyrosine kinases. We demonstrated that when It has been proposed that ligands of receptor tyrosine embryonic day 13.5 rat pancreatic epithelium is cul- tured in the presence of PD98059, an inhibitor of the kinases that are implicated in the control of cell prolifer- mitogen-activated protein (MAP) kinase, epithelial cell ation and differentiation in a large number of organs (2) proliferation is decreased, whereas endocrine cell dif- could also control pancreatic development (3,4). However, ferentiation is activated. On the other hand, in the the exact function of such ligands of receptor tyrosine presence of epidermal growth factor (EGF), an activa- kinases during pancreatic development is not well estab- tor of the MAP kinase pathway, the mass of tissue that lished. It has recently been shown that in mice deficient in develops is increased, whereas the absolute number of epidermal growth factor receptor (EGFR), a member of endocrine cells that develops is decreased. Under this the receptor tyrosine kinase family, pancreatic cell devel- last condition, a large number of epithelial cells prolif- opment was abnormal (5). However, the way by which erate but remain undifferentiated. In a second step, signals mediated by EGFR control the final ␤-cell mass when EGF is removed from the pool of immature pan- creatic epithelial cells, the cells differentiate en masse that develops was not elucidated. Theoretically, ligands into insulin-expressing cells. The total number of insu- of EGFR could control the proliferation of precursor lin-expressing cells that develop can thus be increased cells, their ability to differentiate into mature cells, the by first activating the proliferation of immature epithe- level of proliferation of such mature cells, and, finally, cell lial cells with growth factors, thus allowing an increase survival. in the pool of precursor cells, and next allowing their Recently we developed and characterized an in vitro differentiation into endocrine cells by removing the model of pancreatic development (6,7) that allowed for growth factor. This strategy suggests a possible tissue testing the effects of specific growth factors on the devel- ␤ engineering approach to expanding -cells. Diabetes 50: opment of the endocrine pancreas (8,9). In the present 1571–1579, 2001 study, we used this experimental system to further study the implication of cell proliferation in the control of endocrine cell differentiation. Our data indicate that epi- roliferation of precursor cells and their differen- dermal growth factor (EGF), a ligand of EGFR, acts as a tiation into mature cells represent two crucial growth factor for embryonic pancreatic epithelial cells. processes for the proper development of an When epithelial cell proliferation occurs, endocrine cell Porgan. The pancreatic gland develops from the differentiation is repressed, while putative endocrine pre- gut endodermal epithelium. It is thought that such epithe- cursor cells remain present. Such precursor cells keep the lial precursor cells will first proliferate and then differen- ability to differentiate en masse in insulin-expressing cells tiate into endocrine cells forming the islets of Langerhans when EGF is removed. Taken together, these experiments and exocrine pancreatic tissue. Although progress has indicate that the mass of undifferentiated pancreatic epi- recently been made concerning the transcription factors thelial cells and the balance between epithelial cell prolif- eration and differentiation into insulin-expressing cells can be controlled by signals mediated by receptor tyrosine From the INSERM U457, Hospital R. Debre´, Paris, France. Address correspondence and reprint requests to Raphael Scharfman, PhD, kinases such as EGFR. Such a strategy can thus be used to INSERM U457, Hospital R. Debre´, 48, Boulevard Se´rurier, 75019 Paris, France. increase the final mass of ␤-cells developed. E-mail: [email protected]. Received for publication 19 September 2000 and accepted in revised form 30 March 2001. RESEARCH DESIGN AND METHODS BrdU, bromo-deoxy-uridine; e, embryonic day; EGF, epidermal growth factor; EGFR, EGF receptor; FCS, fetal calf serum; HBSS, Hanks’ balanced Dissections. Pregnant Wistar rats were purchased from Janvier breeding salt solution; MAP, mitogen-activated protein; PBS, phosphate-buffered saline. center (CERJ, Le Genet, France). The morning the vaginal plug was discovered DIABETES, VOL. 50, JULY 2001 1571 GROWTH FACTORS AND ␤-CELL EXPANSION was designated as embryonic day (e) 0.5. Animals had free access to food (MAP) kinase pathway, on cell proliferation and differen- pellets and water. Pregnant rats at 13.5 days of gestation were killed by tiation. Epithelial rudiments were cultured for 3 days with injection of a lethal dose of pentobarbital (Sanofi, Libourne, France). The embryos were harvested, and the dorsal pancreatic buds were dissected as or without PD98059. As shown in Fig. 1A and B,inthe described (10). The pancreatic epithelium was separated from its surrounding presence of PD98059, the size of the rudiments and the mesenchyme, as described previously (6) with minor modifications. Briefly, number of BrdU-positive cells were decreased when com- the stomach, pancreas, and a small portion of the intestine were dissected pared with controls grown for the same period in the together and incubated with 0.5 mg/ml of collagenase A (Boehringer-Mann- heim, Mannheim, Germany) at 37°C for 30 min. They were then washed absence of PD98059. Moreover, the number of BrdU- several times with Hanks’ balanced salt solution (HBSS; Gibco) at 4°C. The positive cells per surface unit was also decreased (P Ͻ epithelium was then mechanically depleted from the surrounding mesen- 0.05) in the presence of PD98059. In fact, while the size of chyme using needles on a 0.25% Agar, 25% HBSS, 75% RPMI (Gibco) gel in a the tissue increased during the 3-day culture period in Petri dish. Organ culture. Pancreatic epithelia were embedded into 500 ␮l of collagen control conditions (Fig. 1B, top left panel; compare col- gel (10% RPMI 10ϫ [Sigma-Aldrich], 80% type I rat tail collagen [2.5 mg/ml; umns 1 and 2), no increase in terms of size of the tissue Sigma-Aldrich], and 10% sodium bicarbonate in NaOH 0.1 mol/l) into four-well was observed during a 3-day culture period in the presence plates (Nunc), as previously described (6,11). Once the gel had polymerized, of PD98059 when compared with uncultured rudiments 500 ␮l of RPMI 1640 (Gibco) containing penicillin (100 U/ml), streptomycin (100 ␮g/ml), HEPES (10 mmol/l), L-glutamin (2 mmol/l), and nonessential (Fig. 1B, top left panel; compare columns 1 and 3). amino acid (1ϫ; Gibco) were added. The medium was supplemented with 1% At the same time, the absolute mass of endocrine cells heat-inactivated fetal calf serum (FCS) (Hyclone). At this concentration of that differentiated in the presence of PD98059 was in- FCS, the development of the endocrine tissue was identical to the one creased when compared with the ones that developed in obtained with 10% FCS. Cultures were maintained at 37°C in a humidified the absence of PD98059 (Fig. 1A and B, bottom panel). In atmosphere of 95% O2/5% CO2. The medium was changed every 2 days, and 50 ng/ml human recombinant EGF (Sigma-Aldrich (diluted in phosphate-buffered fact, while the endocrine cell mass was increased by saline 0.1% bovine serum albumin or its carrier) were added every day. This 1.8-fold during a 3-day culture period in the absence of daily addition and concentration of EGF was chosen because in preliminary PD98059, it was increased 3.3-fold during a 3-day culture experiments it gave the strongest effect on cell differentiation. PD98059 (Calbiochem) was diluted in DMSO and used at 50 ␮mol/l. Comparable DMSO period in the presence of PD98059 when compared with concentrations were made in culture medium. To label cells in the S phase, uncultured rudiments (Fig. 1B, bottom panel). bromo-deoxy-uridine (BrdU; 10 ␮mol/l) was added to the culture medium. At EGF increases epithelial cell mass and represses the indicated times, the pancreatic epithelia were photographed and fixed for endocrine cell differentiation. When e13.5 pancreatic immunohistochemistry, as described below. Immunohistochemistry. Pancreatic rudiments were photographed and fixed epithelial buds were grown in culture in a collagen gel in in formalin 3.7% for 1 h, preembedded in an agarose gel (4% of type VII low the absence of EGF over 7 days, the size of the tissue gellingϪtemperature
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