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Mast Cell Differentiation from Human Peripheral Blood Mononuclear Cells

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Mast Cell Differentiation from Human Peripheral Blood Mononuclear Cells Mast Cell and Myeloid Marker Expression During Early In Vitro Mast Cell Differentiation from Human Peripheral Blood Mononuclear Cells Pia Welker, JuÈrgen Grabbe,* Torsten Zuberbier, Sven Guhl, and Beate M. Henz Departments of Dermatology, Humboldt-University, Berlin, Germany; *Medical University, LuÈbeck, Germany In order to characterize the phenotype of human after 2 wk of culture showed that FceRIa-positive mast cell precursors in the peripheral blood mono- cells were mostly CD14+ (90%),CD64+ (82%),and nuclear fraction and its alterations during in vivo mast CD68+ (52%) on ¯ow cytometry. Intracellular tryp- cell differentiation,cells were studied before and tase activity was ®rst detectable after 1 wk of culture, during culture with stem cell factor or stem cell fac- increased FceRIa expression was only detectable by tor-containing cell supernatants. Prior to culture, week 2. Cultured cells acquired the ability to release 86% of cells were immunoreactive for the monocytic histamine during IgE-dependent stimulation,and marker CD14,slightly fewer for CD11b and CD64, culture with the c-Kit antibody YB5.B8 resulted in a <10% expressed FceRIa,rare cells were CD34+ downregulation of tryptase and FceRIa,but not of (<0,1%), and none stained for CD1, CD33, c-Kit, c-Kit. These data show that human mast cells and tryptase. After 2 wk of culture,there was de novo develop from c-Kit- and tryptase-negative precursors expression of c-Kit (14%±43% positive cells),tryptase in the myelomonocytic fraction of peripheral blood (26%±79%),CD33 (57%),and CD64 (64%),an upre- and that they upregulate,maintain,and share many gulation of FceRIa (23%±52%),CD11b (93%),and phenotypic characteristics of cells from the mono- CD68 (95%),but no expression of CD34. Levels of cyte/macrophage lineage during early phases of in mRNA for FceRIa and c-Kit were detectable prior vitro differentiation. Keywords: c-kit/FceRI/SCF/tryp- to culture and increased during culture,together tase. J Invest Dermatol 114:44±50, 2000 with de novo expression of tryptase. Double staining ast cells are bone marrow-derived, tissue SCF is produced by a number of tissue resident cells including resident cells whose numbers are known to ®broblasts, keratinocytes, endothelial, and bone marrow stroma increase in a wide variety of in¯ammatory and cells, supporting the concept that mast cell precursors can neoplastic conditions (Weber et al, 1995; differentiate in situ in diverse organs including the skin. A MMetcalfe et al, 1997). Mechanisms underlying potential role of SCF in the pathogenesis of mastocytosis has these processes, particularly in the human system, are however also been discussed by different groups (Longley et al, 1993; largely unclear (Denburg, 1995; Czarnetzki et al, 1996). One Castells et al, 1996; Henz, 1998). As suggested by its name, possible way for mast cells to increase at tissue sites might SCF is however not mast cell speci®c, as it also affects a involve the in¯ux of precursors from the peripheral blood into number of other cells expressing its c-Kit receptor, including the tissue, with subsequent differentiation of the cells under the hematopoietic stem cells, melanocytes, and germ cells (Grabbe in¯uence of locally secreted growth factors. Stem cell factor et al, 1994a). (SCF), also known as mast cell growth factor, Steel factor, or c- We and others have shown in the past that cells expressing all Kit ligand, has been identi®ed as a potent mast cell growth major features of mast cells can be induced in cultures of the factor (Zsebo et al, 1990; Williams et al, 1990; Takagi et al, monocytic fraction from human peripheral blood (PBMC) under 1990) and appears to be the main mast cell differentiation factor the in¯uence of SCF or SCF-containing ®broblast- and keratino- identi®ed so far in humans (reviewed in Grabbe et al, 1994a). cyte-derived mast cell conditioning medium (Czarnetzki et al, 1983, 1984; Valent et al, 1992; Agis et al, 1993; Grabbe et al, 1994b; Welker et al, 1995). In the bone marrow and in cord blood, mast Manuscript received September 19, 1997; revised September 14, 1999; accepted for publication September 20, 1999. cells have been shown to developfrom CD34+, SCF-responsive, Reprint requests to: Dr. Pia Welker, ChariteÂ, Campus Virchow, multipotent hematopoietic progenitor cells (Kirshenbaum et al, Department of Dermatology, Augustenburger-Platz 1, D 13344 Berlin, 1992; Agis et al, 1993; Rottem et al, 1994; Huang and Terstappen, Germany. Email: [email protected] 1995). The phenotype of the committed, speci®c mast cell Abbreviations: APAAP, alkaline phosphatase anti-alkaline phosphatase; precursor remains elusive however. In peripheral blood that serves FceRI, high af®nity IgE receptor; HPLC, high performance liquid as a direct source of mast cell precursors for diverse organs, chromatography; HFS, human ®broblast supernatants; HKS, human keratinocyte supernatants; Ig, immunoglobulin; LCS, L-cell ®broblast including the skin, CD34+ cells are extremely rare and yield only a supernatant; NGF, nerve growth factor; PBMC, peripheral blood minor fraction of mast cells during in vitro culture, whereas CD14± monocytic cells; SCF, stem cell factor. cells have been described to provide the main proportion of these 0022-202X/00/$15.00 ´ Copyright # 2000 by The Society for Investigative Dermatology, Inc. 44 VOL. 114, NO. 1 JANUARY 2000 MAST CELL PRECURSOR 45 cells (Valent, 1994). In nasal mucosa, a c-Kit+, tryptase±,FceRI± Flow cytometric analysis For ¯ow cytometric analysis, 5 3 105 cells cell has recently been identi®ed and proposed to serve as a were incubated for 60 min at 4°C with the monoclonal receptor antibodies committed mast cell precursor (Kawabori et al, 1997). in 50 ml of phosphate-buffered saline (PBS), containing human AB serum (Seromed) (0.1%). After two washes with PBS, cells were incubated for In order to further delineate the phenotype of the mast cell 45 min at 4°C with a 1:20 dilution of ¯uorescein isocyanate (FITC)- precursor in peripheral blood, which would serve as source of mast conjugated anti-mouse IgG (DAKO, Denmark) or phycoerythrine (PE)- cells in diverse organs including the skin, this study was designed to conjugated anti-mouse IgG (Dianova, Hamburg, Germany). Following focus on the identi®cation of several typical mast cell markers and two washes, cells were suspended in 400 ml PBS containing 0.1% NaN3, of monocytic markers on PBMC prior to and during culture in the ®xed with 50 ml of a 37% formaldehyde solution, and analysed on an presence of SCF or mast cell growth factor-containing condition- EPICES Pro®le ¯ow cytometer (Coulter, Krefeld, Germany). Negative ing media. The data con®rm the previously suggested close controls were done in the absence of antibody, with IgG and isotype- relationship between mast cells and peripheral blood myelomono- matched desmin antibody D33 (DAKO). For ¯ow cytometric analysis, the cytic cells (Czarnetzki et al, 1992, 1983, 1984; Valent et al, 1989). elite workstation software (Coulter) was used. They furthermore underline the central role of SCF compared with Tryptase activity The enzyme activity of mast cell tryptase was detected possible additional mast cell growth factors in this process. by cleavage of the peptide Z-Gly-Pro-Arg-pNA (4 mM) in the presence of heparin (5 mg per ml) and a-1-antitrypsin (2 mg per ml) (all from Sigma, St MATERIALS AND METHODS Louis, MO), as described before (Harvima et al, 1988). Cells were lysed by three cycles of freezing and thawing for determination of intracellular Cells PBMC were prepared from peripheral blood of different healthy tryptase. Activity was expressed as mU per 106 cells. donors by a sequence of differential centrifugation on Ficoll-Hypaque, In order to analyse tryptase activities of FceRI-positive and negative adherence to polystyrene culture ¯asks for 2 h, and subsequent washing cells, PBMC cultured for 14 d were separated using the FceRI antibody with RPMI containing 10% fetal calf serum (both from Seromed, Berlin, 29C6 and magnetic cell sorting with microbeads (MACS) (Miltenyi Biotec, Germany) to remove nonadherent cells (Grabbe et al, 1994b). Human Bergisch Gladbach, Germany), as described before (Zuberbier et al, 1999), leukemic mast cells (HMC-1) were kindly provided by J.H. Butter®eld, yielding >95% purity of either cell population. Minneapolis, U.S.A. (Butter®eld et al, 1988) and human basophilic leukemic cells (KU 812 cells) (Kishi, 1985) were from the Research Assessment of intracellular and released histamine Histamine was Institute in Borstel, Germany. quanti®ed in perchloric acid lysed cells and in cell supernatants, using a modi®ed automated ¯uorometric method as described (Zuberbier et al, Cell culture Cells were kept routinely in mast cell growth medium 1995). For studies of histamine release, cells were preincubated with IgE consisting of Iscove's medium (GIBCO, Eggenstein, Germany) and (1 mg per ml, Calbiochem, Bad Soden, Germany) for 30 min at 37°C, 30% horse serum (Seromed) because this basic medium has been followed by addition of anti-IgE (4000 U per ml, Behring, Marburg, proven in the past to be optimal for supporting the activity of mast cell Germany) and another 30 min incubation. Samples were kept at ±20°C differentiation factors (Czarnetzki et al, 1983). For mast cell until analysis. differentiation, L-cell ®broblasts (LCS), human ®broblast (HFS), or HaCaT keratinocyte supernatants (HKS), obtained from con¯uent culture of cells after a 5 d culture in Dulbecco's minimal essential Isolation of RNA Cells from days 0 and 14 were lysed with 3 M lithium medium (DMEM, GIBCO) with 5% newborn calf serum or 10% fetal chloride and 6 M urea, centrifuged at 20 000 rpm for 60 min and extracted calf serum (both GIBCO), were added to the basic mast cell growth with phenol-chloroform, according to Sambrook et al (1989a).
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