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The Journal of Immunology, 1998, 161: 5143-5146.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Generation of a Novel Stem Cell Factor-Dependent Mast Cell Progenitor1

Qian Yuan*,{dagger},§, Michael F. Gurish*,§, Daniel S. Friend*,{ddagger},§, K. Frank Austen*,§,¶ and Joshua A. Boyce2,*,{dagger},§,¶

Departments of * Medicine, {dagger} Pediatrics, and {ddagger} Pathology, Harvard Medical School; § Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital; and Partners Asthma Center, Boston, MA 02115


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Tissue mast cell development requires stem cell factor (SCF), whereas helminth-induced intestinal mucosal mast cell hyperplasia also requires T cell-derived factors such as IL-3. We generated progenitor mast cells (PrMC) from mouse bone marrow cells (BMC) in vitro with a triad of SCF, IL-6, and IL-10 that exhibit IL-3-mediated mitogenic and maturation responses. SCF/IL-6/IL-10 transiently elicited a cell subpopulation with the phenotype (c-kithighThy-1low) of fetal blood promastocytes at 3 wk of culture that progressed within 1 wk to Fc{epsilon}RI-bearing PrMC, designated PrMCTriad. PrMCTriad lacked mouse mast cell carboxypeptidase A (mMC-CPA) protein, required SCF for IL-3-driven thymidine incorporation, and responded to SCF plus IL-3 with strong mMc-CPA immunoreactivity, clarifying distinct sequential roles for SCF and IL-3 in mast cell development. PrMCTriad, arising from BMC through promastocytes, are metamastocytes that acquire microenvironmentally determined phenotypic features.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Committed progenitor mast cells (PrMC)3 derive from pluripotent hemopoietic cells in bone marrow (1, 2, 3) and undergo terminal maturation in their ultimate tissue destinations after a circulating phase. The circulating PrMC of mouse fetal blood (promastocytes) are identified by weak metachromatic staining with toluidine blue, strong surface expression of the c-kit receptor for stem cell factor (SCF), and weak expression of Thy-1 (c-kithighThy-1low) (4). WBB6F1/J-kitW/kitW-v mice, which are genetically deficient in c-kit (c-kitW/Wv mice), and WCB6F1/J-MgfSl/MgfSl-dmice, which are genetically deficient in the membrane-bound isoform of SCF (Mgf Sl/Sld mice), have markedly diminished numbers of tissue mast cells under basal conditions (1, 5, 6). The mast cell deficiency of c-kitW/Wv mice can be corrected by the transplantation of bone marrow cells (BMC) from +/+ littermates with normal c-kit function, implying that PrMC development from uncommitted BMC depends on the interaction of SCF with c-kit and that this interaction is sufficient to maintain basal tissue mast cell levels (1). The capacity of mice to develop a reactive intestinal mucosal mast cell hyperplasia in response to helminth infection, however, requires not only the intact interaction of SCF and c-kit (2) but also T cell-derived factors, including IL-3 (7, 8, 9). Conversely, IL-3 is not required to maintain basal levels of tissue mast cells (7). Thus, stromal cell-derived SCF and T cell-derived IL-3 have distinct roles in mast cell development, with SCF maintaining a pool of committed PrMC and IL-3 providing synergy with SCF for circumstances of T cell-driven reactive intestinal mucosal mast cell hyperplasia. The finding that either cytokine alone elicits mast cell growth from unfractionated mouse BMC in vitro (10, 11) reflects the presence in normal mice of BMC subpopulations capable of mast cell growth in response to each cytokine. The fact that SCF and IL-3 do not act on distinct pluripotent BMC subsets, but are operative at different stages of mast cell lineage development, is revealed by the identification of a SCF-dependent, IL-3-responsive metamastocyte population.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Reagents and Abs

Recombinant mouse SCF (12), IL-10, and IL-3 were acquired through expression in baculovirus (13, 14). Recombinant mouse IL-6 was purchased from PeproTech Inc. (Rocky Hill, NJ). The following rat anti-mouse Abs were used: FITC-conjugated anti-mouse CD117 (c-kit) (Clone 2B8); R-phycoerythrin (R-PE)-conjugated anti-mouse CD13 (Clone R3-242), which recognizes the same mouse aminopeptidase N as the K-1 Ab (15, 16); R-PE-conjugated anti-mouse CD90 (Thy-1); FITC-conjugated rat IgG2b; R-PE-conjugated rat IgG1; purified unconjugated anti-mouse CD16/CD32 (Clone 2.4G2); anti-mouse CD23 (Clone B3B4); purified rat IgG1, IgG2a, and IgG2b; and FITC-conjugated anti-mouse IgE were purchased from PharMingen (San Diego, CA). FITC-conjugated goat anti-rat IgG was purchased from BioSource International (Camarillo, CA).

Isolation, fractionation, and culture of BMC

Mouse BMC from 6- to 8-wk-old female BALB/c mice (The Jackson Laboratory, Bar Harbor, ME) were separated on the basis of the presence (BMCS+) or absence (BMCS-) of a very early hemopoietic lineage surface marker, Sca-1 (17) using MultiSort Sca-1 MicroBeads provided in the Sca-1 MultiSort Kit using the manufacturer’s protocol (Miltenyi Biotec, Sunnyvale, CA). The purity of the cell populations was confirmed using flow cytometry, with the adherent fraction being >90% Sca-1+ and the flowthrough being <5% Sca-1+ (not shown). The freshly isolated BMCS+ and BMCS- were suspended in 25-cm2 flasks (Corning, Corning, NY) at a concentration of 1 x 105 cells/ml of enriched medium (RPMI 1640 containing 100 U/ml penicillin, 100 µg/ml streptomycin, 10 µg/ml gentamicin, 2 mM L-glutamine, 0.1 mM nonessential amino acids, 50 µM 2-ME (Sigma, St. Louis, MO), and 10% FCS to sustain cell viability (Sigma)) supplemented with either 100 U/ml of IL-3 or the triad of 100 ng/ml SCF, 50 ng/ml IL-6, and 100 U/ml IL-10. IL-10 was added because of its costimulatory activity for SCF-driven (18) and IL-3-driven (19) mast cell growth; IL-6 was added because of its costimulatory properties in SCF-dependent human mast cell development in vitro (20). Cells were fed with fresh medium and cytokines weekly and were dispersed to maintain a cell concentration below 1 x 106 cells/ml. New culture flasks were used when the total volume in each flask exceeded 10 ml. Cells were counted and stained with toluidine blue weekly as described (18).

Assays for [3H]thymidine incorporation and cytofluorographic analyses

[3H]Thymidine was incorporated by 0.2 x 105 cells in triplicate experiments as described (18). The cytokines used in the 7-day proliferation assays and their final concentrations were SCF (100 ng/ml), IL-6 (50 ng/ml), IL-10 (100 U/ml), IL-3 (100 U/ml), IL-5, IL-2, and granulocyte-macrophage (GM)-CSF (10 ng/ml each). Cytofluorographic analyses were performed on samples of 5 x 105 cells as described (21). The cells were washed once with cold HBSS/FCS, resuspended in 0.25 ml of cold HBSS, and analyzed on a FACSort machine (Becton Dickinson, Oxnard, CA). The staining for Fc{epsilon}RI expression was performed as described (22).

Immunocytochemistry and electron microscopy

Cytocentrifugation slides were prepared with 104 cells per glass slide (Fisher Scientific) and were fixed in 4% paraformaldehyde (Polysciences, Warrington, PA) in PBS for 10 min at room temperature. After blocking and incubation with an affinity-purified rabbit anti-mouse polyclonal Ab against a mMC-CPA-specific peptide (23), immunocytochemical staining was conducted with alkaline phosphatase as the chromogenic reporter (24).

For electron microscopy, glutaraldehyde-fixed, epoxy-embedded pellets of 1–2 x 106 cells were processed by standard procedures (25) and examined with a JEOL 100 CX transmission electron microscope operating at 80 KV.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
When BMCS+ and BMCS- were cultured with the cytokine triad of SCF/IL-6/IL-10, total cells (Fig. 1GoA) and toluidine blue-positive cells (Fig. 1GoB) peaked at 2–3 wk. The numbers of toluidine blue-positive cells from BMCS+ and BMCS- were similar, implying that mast cell growth in response to SCF did not depend on the developmental stage of the BMC. Both total cell numbers (Fig. 1GoA and toluidine blue-positive cell numbers (Fig. 1GoB) declined between wks 2 and 4 in the triad-driven cultures, suggesting apoptosis at a different rate than that seen in the IL-3-driven cultures. An increment in purely toluidine blue-positive cells occurred between weeks 6 and 7, implying ongoing cell renewal in the triad-driven cultures. In contrast, when replicate cultures were maintained in IL-3 alone, fourfold fewer toluidine blue-positive cells arose from BMCS+ than from BMCS- (Fig. 1GoB), possibly reflecting greater numbers of IL-3-responsive committed PrMC within the BMCS-. The SCF/IL-6/IL-10-driven cells from BMCS+ acquired uniform metachromasia with toluidine blue more slowly than those from BMCS- (Fig. 1GoC), likely reflecting different kinetics of development from different progenitor cell stages. Both SCF/IL-6/IL-10-driven groups lagged behind their IL-3-driven replicates, consistent with preferential actions of IL-3 on later committed PrMC. Unlike fetal blood promastocytes, which require both SCF and IL-3 for mitogenic responses (4), these IL-3-responsive BMC did not require the costimulatory effects of exogenous SCF for mast cell proliferation in vitro, consistent with prior observations with cultures of unfractionated BMC (10). The markedly different yields of PrMCIL-3 from the two BMC populations may reflect the ability of accessory cells in the BMCS- to generate endogenous growth factors that substitute for SCF under these culture conditions. Indeed, high doses (100 U/ml) of IL-3 induce full mast cell proliferation in vitro from BMC from c-kitW/Wv or Mgf Sl/Sld mice (26), and continuous infusion of IL-3 into the peritoneal cavity for 28 days restores the number of skin mast cells in c-kitW/Wv mice to normal levels (27). Nonetheless, the absolute requirements for SCF and c-kit in physiologic mast cell development (1, 2, 5, 6) and the requirements for both SCF and IL-3 in intestinal reactive hyperplasia (7) and in mast cell development in vitro from fetal blood promastocytes (4) indicate synergistic but distinct roles for SCF and IL-3 in vivo when the inductive influences are physiologic.



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  		FIGURE 1. Total cell numbers (A), total numbers of metachromatic cells (B), and percentage of metachromatic cells (C) derived from 0.5 x 106 mouse BMC fractionated into Sca-1+ (BMCS+) and Sca-1- (BMCS-) populations and cultured for 7 wk in the presence of SCF/IL-6/IL-10 or IL-3. Open symbols represent PrMCIL-3 derived from either BMCS+ (squares) or BMCS- (circles). Closed symbols represent PrMCTriad derived from either BMCS+ (squares) or BMCS- (circles). Results are the mean ± SEM of three independent experiments. The asterisk indicates statistically significant differences in the numbers of metachromatic cells obtained with IL-3 from BMCS+ and from BMCS-.

 
Circulating mouse fetal blood promastocytes are defined by a membrane phenotype of c-kithighThy-1low and lack surface expression of Fc{epsilon}RI (4). Mouse mast cells are distinguished from basophils by their expression of the membrane aminopeptidase CD13 (15, 16). Unlike the IL-3-driven cultures, which were uniformly c-kitvery highThy-1neg and Fc{epsilon}RI positive at 3 wk (Fig. 2Go), SCF/IL-6/IL-10-driven cultures contained not only a c-kitveryhighThy-1neg population, but also a c-kithighThy-1low population at 3 wk (Fig. 2GoA, populations c and b, respectively; each accounting for 20–30% of the cells) at a time when Fc{epsilon}RI expression was still absent on approximately two-thirds of the cells (Fig. 2GoC). The c-kithighThy-1low promastocyte-like population had disappeared by 4 wk, by which time PrMCTriad were identical to PrMCIL-3 in the expression of c-kit, CD13, and Fc{epsilon}RI and were more than 95% Thy-1 negative, irrespective of the starting BMC population (Fig. 2Go, B and C).



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  		FIGURE 2. Cytofluorographic analysis of PrMC. A, Two color analysis for simultaneous expression of c-kit (horizontal axes) and Thy-1 (vertical axes) of PrMC grown from BMCS+ or BMCS- under the indicated cytokine conditions at 3 wk. Note three predominant populations in the cultures driven by SCF/IL-6/IL-10: a) c-kitnegThy-1neg, b) c-kithighThy-1low, and c) c-kitvery highThy-1neg. B, Simultaneous expression of c-kit (horizontal axes) and Thy-1 (top row, vertical axes) or CD13 (bottom row, vertical axes) in PrMC cultured for 4 wk under the indicated conditions. Near homogeneity is evident in each cell group for c-kit, Thy-1, and CD13. C, Single color cytofluorographic analysis of Fc{epsilon}RI expression (shaded curve) at 3 (top row) and 4 (bottom row) wk for the corresponding cell groups. Staining with an irrelevant isotype-matched control Ab is represented by the unshaded curve. Results are representative of three independent experiments.

 
Like fetal blood promastocytes (4), the 4-wk-old PrMCTriad incorporated significant amounts of thymidine only in the presence of SCF and IL-3, whereas PrMCIL-3 responded well to IL-3 alone or with SCF (Fig. 3Go), reflecting possible differences in IL-3 receptor expression or function between the two PrMC groups. The findings that neither PrMC population incorporated thymidine in response to IL-5, IL-2, or GM-CSF (data not shown) supports the commitment of each population to the mast cell lineage. The recognition of a transient subpopulation exhibiting the phenotype of the circulating fetal blood promastocytes (4) with SCF/IL-6/IL-10, but not with IL-3, is again compatible with a capacity of SCF to recruit for the mast cell lineage from an uncommitted BMC subpopulation. The requirement for both SCF and IL-3 for further proliferation supports the ontogenic relationship of PrMCTriad to promastocytes and suggests that PrMCTriad are metamastocytes (direct descendants of promastocytes).



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  		FIGURE 3. Incorporation of [3H]thymidine by PrMCIL-3 and by PrMCTriad derived from BMCS+ and from BMCS-. Four-wk-old cells were harvested, extensively washed, and recultured under the indicated conditions of cytokine supplementation for 7 days. No thymidine was incorporated in response to IL-2, GM-CSF, or IL-5 (not shown). The depicted experiment was performed in triplicate and is typical of seven independent studies.

 
Promastocytes purified from mouse fetal blood and cultured with SCF and IL-3 develop into immature mast cells (4). Whereas PrMCIL-3 possess a mixture of electron-dense granules and vesicular profiles typical of mast cells derived in vitro with IL-3 (25) (Fig. 4GoA), almost all the PrMCTriad had large granules filled with electron-lucent vesicular matrix and little dense substance (Fig. 4GoJ). The ultrastructural features of PrMCTriad strongly resemble those of the immature mast cells developed in vitro directly from fetal blood promastocytes by culture with SCF and IL-3 (4). While both PrMCTriad and PrMCIL-3 had metachromatic granules (Fig. 4Go, B and F), the granules of PrMCTriad were larger and more loosely organized than those of PrMCIL-3. These features appear to characterize the granules of metamastocytes and precede the development of electron-dense structures that characterize mature tissue mast cells.



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  		FIGURE 4. Transmission electron micrographs (A, J) and cytocentrifugation slides (B–I) of PrMCIL-3 (left panels) and of PrMCTriad (right panels) from a 4-wk culture of BMCS+. Note different 20-µm scales. PrMCIL-3 show a mixture of electron-dense structures and vesicular profiles (A), while PrMCTriad possess large granules filled with electron-lucent vesicular matrix and little dense substance (J). Both cell groups show metachromasia with toluidine blue (B, F), but the metachromatic granules are larger and more loosely organized in PrMCTriad). Immunostaining with a rabbit anti-mouse mMC-CPA peptide IgG (C, G) revealed striking differences in immunoreactivity. PrMCIL-3 cultured in the presence of SCF/IL-6/IL-10 for an additional week retained their original mMC-CPA staining intensity (D), whereas PrMCTriad exhibited a dramatic induction of mMC-CPA immunoreactivity after 1 wk of exposure to SCF + IL-3 (H). Neither cell population reacted with preimmune IgG (E, I). The depicted immunocytochemical experiment is representative of four independent studies. PrMC grown from BMCS- were similar.

 
Fetal blood promastocytes express mRNA-encoding mMC-CPA detectable by RT-PCR (4), and incremental acquisition of mMC-CPA protein is considered a marker of mast cell differentiation and maturation (23). PrMCIL-3 were strongly immunoreactive for mMC-CPA (Fig. 4GoC) as anticipated from earlier studies with cultures of unfractionated bone marrow (10). Unexpectedly, however, PrMCTriad were negative for mMC-CPA (Fig. 4GoG). The marked induction of mMC-CPA immunoreactivity in 4-wk-old PrMCTriad stimulated with SCF and IL-3 for 1 wk is therefore compatible with a maturation-related event (Fig. 4GoH). Conversely, the fact that PrMCIL-3 remained strongly reactive for mMC-CPA after 1 wk of exposure to SCF/IL-6/IL-10 suggests that this cytokine combination did not suppress mMC-CPA expression (Fig. 4GoD). Thus metamastocytes, like promastocytes, are likely part of a sequence of mast cell development beginning in the bone marrow. The initial stages of this sequence are SCF-dependent and result in cell populations (promastocytes and metamastocytes) that respond to the synergistic combination of SCF and IL-3 with mitogenesis and mMC-CPA expression. The reconstitution of peritoneal mast cells by the i.v. or i.p. infusion of promastocytes supports the importance of this SCF-dependent pathway for establishing basal levels of tissue mast cells (4). In contrast, the direct recruitment of PrMC by IL-3 alone reflects an alternative pathway for mast cell development that does not operate under most physiologic circumstances (7).


   Footnotes
 
1 This work was supported by National Institutes of Health Grants AI-01304, AI-31599, AI-22531, and HL-36110, and by grants from the Hyde and Watson Foundation and from the Immunology Research Institute of New England. J.A.B. is the recipient of a Basic Investigator Award from Glaxo Wellcome. Back

2 Address correspondence and reprint requests to Dr. Joshua A. Boyce, Brigham and Women’s Hospital, Harvard Medical School, Smith Building, Room 618, 1 Jimmy Fund Way, Boston, MA 02115. E-mail address: Back

3 Abbreviations used in this paper: PrMC, progenitor mast cells; SCF, stem cell factor; CPA, carboxypeptidase A; BMC, bone marrow cells; PE, phycoerythrin; GM-CSF, granulocyte-macrophage CSF. Back

Received for publication July 6, 1998. Accepted for publication September 10, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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H. Ochi, W. M. Hirani, Q. Yuan, D. S. Friend, K. F. Austen, and J. A. Boyce
T Helper Cell Type 2 Cytokine-Mediated Comitogenic Responses and Ccr3 Expression during Differentiation of Human Mast Cells in Vitro
J. Exp. Med., July 19, 1999; 190(2): 267 - 280.
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