Stem Cell Factor in Mast Cells and Increased Mast Cell Density in Idiopathic and Ischemic Cardiomyopathy

Changes in the density and distribution of pulmonary mast cells were determined in six mammalian species exposed to hypobaric hypoxia (PB = 435 Torr) for 19–48 days. Control animals were studied at 1,600 m (PB = 635 Torr). Total lung mast cell hyperplasia was observed only in calves exposed to high altitude. Pigs, rats, and sheep exhibited small, but insignificant, increases in mast cell density. Perivascular mast cell proliferation adjacent to vessels of 30–500 mum in diameter was seen in both calves and pigs. Bronchial, alveolar septal, and systemic tissue (tongue) mast cell hyperplasia was not observed in any of the species. Three indices of pulmonary hypertension (right ventricular hypertrophy, medial thickness of pulmonary arteries, and pulmonary arterial pressure) correlated with perivascular mast cell density. The findings indicate that perivascular mast cell proliferation may relate more to the morphological pulmonary vascular changes and to pulmonary hypertension than to hypoxia, leading to the speculation that mast cells increase in number in response to the hypertension, rather than to mediate and maintain the hypertension.

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The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. Evidence that signaling through the c-kit receptor can induce expression of cellular function.

Journal of Experimental Medicine ◽

10.1084/jem.175.1.245 ◽

1992 ◽

Vol 175 (1) ◽

pp. 245-255 ◽

Cited By ~ 88

Author(s):

B K Wershil ◽

M Tsai ◽

E N Geissler ◽

K M Zsebo ◽

S J Galli

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Mast Cells ◽

Stem Cell Factor ◽

Cell Activation ◽

Mast Cell Activation ◽

Tyrosine Kinase Receptor ◽

Kit Ligand ◽

Kit Receptor

Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function.

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Cofactors are essential for stem cell factor-dependent growth and maturation of mast cell progenitors: comparative effects of interleukin- 3 (IL-3), IL-4, IL-10, and fibroblasts

Blood ◽

10.1182/blood.v85.1.57.bloodjournal85157 ◽

1995 ◽

Vol 85 (1) ◽

pp. 57-65 ◽

Cited By ~ 77

Author(s):

D Rennick ◽

B Hunte ◽

G Holland ◽

L Thompson-Snipes

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Cell Differentiation ◽

Mast Cells ◽

Colony Formation ◽

Stem Cell Factor ◽

Interleukin 10 ◽

Interleukin 4 ◽

Phenotypic Change ◽

Interleukin 3

Stem cell factor (SCF) possesses many mast cell-stimulating activities, including the ability to support the growth of mucosal-like mast cells (MMCs) and connective tissue mast cells (CTMCs). However, this study shows that, in the absence of accessory cells, SCF does not stimulate the clonal growth of primitive mast cell progenitors. Nevertheless, SCF exhibited potent growth-promoting effects when combined with the cytokines interleukin-3 (IL-3), interleukin-4 (IL-4), and interleukin- 10 (IL-10). Our comparative studies have shown that optimal mast cell colony formation occurs when both IL-4 and IL-10 are combined with SCF. However, in the presence of SCF, these two cofactors appear to mediate different effects. IL-4 was more efficient than IL-10 in costimulating the initiation of SCF-dependent colony formation by mast cell progenitors and in sustaining the proliferation of newly generated progeny. On the other hand, IL-4 was less efficient than IL-10 in supporting mast cell differentiation, as evidenced by morphology, cell enlargement, and granule production. Although the actions of IL-4 and IL-10 were not equivalent, additional experiments indicated that their ability to serve as early- and late-acting factors, respectively, were complimentary. We have also found that the mast cells generated in colonies stimulated by IL-4, IL-10, and SCF produced high levels of histamine (6–8 pg per cell). None of the mast cells generated in our cultures synthesized heparin. A phenotypic change from safranin- negative to safranin-positive cells associated with heparin-producing CTMCs was accomplished after coculture of the mast cells with fibroblast cell lines derived from normal mice or from SI/SId mice plus soluble factors. Collectively, our observations demonstrate that SCF acts as a competence factor for mast cell progenitor growth. In addition, the ability of SCF to support certain stages of mast cell differentiation is profoundly influenced by interactions with specific cofactors.

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Eotaxin Modulates Myelopoiesis and Mast Cell Development From Embryonic Hematopoietic Progenitors

Blood ◽

10.1182/blood.v92.6.1887 ◽

1998 ◽

Vol 92 (6) ◽

pp. 1887-1897 ◽

Cited By ~ 43

Author(s):

Elizabeth J. Quackenbush ◽

Barry K. Wershil ◽

Vincent Aguirre ◽

Jose-Carlos Gutierrez-Ramos

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Mast Cells ◽

Stem Cell Factor ◽

Fetal Liver ◽

Hematopoietic Progenitors ◽

Embryonic Tissues ◽

Pathological Conditions ◽

Gi Protein ◽

American Society

Abstract Eotaxin is a potent chemoattractant for eosinophils during inflammation and allergic reactions in the adult, but its role in the embryonic development of the hematopoietic system has not been examined. We report here that eotaxin and its receptor, CCR-3, are expressed by embryonic tissues responsible for blood development, such as fetal liver (FL), yolk sac (YS), and peripheral blood. We found that eotaxin acts synergistically with stem cell factor to accelerate the differentiation of embryonic mast cell progenitors, and this response can be suppressed by pertussis toxin, an inhibitor of chemokine-induced signaling through Gi protein and chemotaxis. Eotaxin promotes the differentiation of fetal mast cell progenitors into differentiated mast cells as defined by the expression of mast cell specific proteases. Furthermore, in combination with stem cell factor (SCF), it promotes the growth of Mac-1+myeloid cells from embryonic progenitors. These studies suggest that eotaxin may be involved in the growth of granulocytic progenitors and the differentiation and/or function of mast cells during embryogenesis and/or pathological conditions that induce high levels of eotaxin, such as allergic responses. © 1998 by The American Society of Hematology.

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Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00622.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. H1251-H1257 ◽

Cited By ~ 24

Author(s):

David B. Murray ◽

Jason D. Gardner ◽

Gregory L. Brower ◽

Joseph S. Janicki

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Density ◽

Volume Fraction ◽

Volume Overload ◽

Receptor Antagonism ◽

Collagen Volume Fraction ◽

Endothelin 1 ◽

Mast Cell Density ◽

Chronic Volume Overload

The objective of this study was to investigate the effect a nonselective endothelin-1 (ET-1) receptor antagonist (bosentan) had on the acute myocardial remodeling process including left ventricular (LV) mast cells and matrix metalloproteinase (MMP) activity secondary to volume overload. Additionally, we investigated the overall functional outcome of preventative endothelin receptor antagonism during 14 days of chronic volume overload. LV tissue from sham-operated (Sham), untreated-fistula (Fist), and bosentan (100 mg·kg−1·day−1)-treated animals (Fist + Bos) was analyzed for mast cell density, MMP activity, and myocardial collagen volume fraction at 1 and 5 days after the creation of an aortocaval fistula. When compared with untreated fistulas, bosentan treatment prevented the marked increase in LV mast cell density at 1 day postfistula (3.1 ± 0.3 vs. 1.3 ± 0.3 LV mast cells/mm2, Fist vs. Fist + Bos, P ≤ 0.01). Additionally, the substantial increase in MMP-2 activation in the untreated fistula at 1 day was prevented following bosentan treatment (1.6 ± 0.3 vs. 0.9 ± 0.1 arbitrary activity units, Fist vs. Fist + Bos, P ≤ 0.01). The marked decrease in collagen volume fraction seen in the Fist group (1.4 ± 0.1 vs. 0.8 ± 0.1% myocardial tissue, Sham vs. Fist, P ≤ 0.01) was significantly attenuated following bosentan treatment at both the 1- and 5-day time points. Lastly, a 2-wk preventative treatment with bosentan resulted in significant attenuation of the increase in LV end-systolic and -diastolic volumes compared with those in untreated fistula hearts. In summary, nonselective ET-1 antagonism prevents the acute increases in cardiac mast cell density and MMP activation induced secondary to chronic volume overload. By preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits in the first 2 wk of chronic volume overload. Accordingly, these results are the first to demonstrate that cardiac mast cells are responsive to the endogenous endothelin system in vivo. Another novel finding from this study is that chronic nonspecific endothelin antagonism may inadvertently potentiate ET-1-mediated signaling.

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Regulatory effects of stem cell factor and interleukin-4 on adhesion of human mast cells to extracellular matrix proteins

Blood ◽

10.1182/blood.v99.3.966 ◽

2002 ◽

Vol 99 (3) ◽

pp. 966-972 ◽

Cited By ~ 47

Author(s):

Axel Lorentz ◽

Detlef Schuppan ◽

Andreas Gebert ◽

Michael P. Manns ◽

Stephan C. Bischoff

Keyword(s):

Extracellular Matrix ◽

Mast Cell ◽

Stem Cell ◽

Cell Adhesion ◽

Mast Cells ◽

Stem Cell Factor ◽

Collagen I ◽

Interleukin 4 ◽

Human Mast Cells ◽

Ecm Proteins

Abstract Mast cells are inflammatory and immunoregulatory cells resident in tissues. They develop from bone marrow-derived progenitor cells that enter the tissue through the blood circulation. The specific localization and migration of mast cells in tissues is dependent on their interaction with extracellular matrix (ECM) proteins. Adhesion of human mast cells isolated from intestinal mucosa and cultured in the presence of stem cell factor (SCF) to ECM proteins is analyzed. It was observed that SCF is a unique cytokine enhancing mast cell adhesion to all tested ECM proteins (fibronectin, laminin, collagen I, III, IV, VI, XIV) up to 5-fold, particularly to fibronectin (54% ± 12% of mast cells) and to denatured collagens (40% ± 12% on cyanogen bromide-cleaved peptides of collagen I). Most noteworthy, preculture of mast cells with interleukin-4 (IL-4), in addition to SCF, reduced their potency to adhere to ECM proteins to one third compared to mast cells cultured with SCF alone. Mast cell adhesion was preferentially mediated by β1 integrins, and most cells expressed the ECM-binding integrins α2β1, α3β1, α4β1, α5β1, and αVβ3. SCF-induced mast cell adhesion was totally blocked by wortmannin and apigenin, indicating an involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase, and it was related to an up-regulation of the HUTS-21 β1 epitope, which is associated with an activated conformation of β1. In conclusion, these data indicate that SCF induces the adhesion of cultured mast cells to ECM proteins, whereas IL-4 may promote detachment from the ECM.

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Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo.

Journal of Experimental Medicine ◽

10.1084/jem.183.6.2681 ◽

1996 ◽

Vol 183 (6) ◽

pp. 2681-2686 ◽

Cited By ~ 190

Author(s):

J J Costa ◽

G D Demetri ◽

T J Harrist ◽

A M Dvorak ◽

D F Hayes ◽

...

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Mast Cells ◽

Stem Cell Factor ◽

Serum Levels ◽

Human Mast Cell ◽

Tyrosine Kinase Receptor ◽

Kit Ligand ◽

Wheal And Flare

Stem cell factor (SCF), also known as mast cell growth factor, kit ligand, and steel factor, is the ligand for the tyrosine kinase receptor (SCFR) that is encoded by the c-kit proto-oncogene. We analyzed the effects of recombinant human SCF (r-hSCF, 5-50 micrograms/kg/day, injected subcutaneously) on mast cells and melanocytes in a phase I study of 10 patients with advanced breast carcinoma. A wheal and flare reaction developed at each r-hSCF injection site; by electron microscopy, most dermal mast cells at these sites exhibited extensive, anaphylactic-type degranulation. A 14-d course of r-hSCF significantly increased dermal mast cell density at sites distant to those injected with the cytokine and also increased both urinary levels of the major histamine metabolite, methyl-histamine, and serum levels of mast cell alpha-tryptase. Five subjects developed areas of persistent hyperpigmentation at r-hSCF injection sites; by light microscopy, these sites exhibited markedly increased epidermal melanization and increased numbers of melanocytes. The demonstration that r-hSCF can promote both the hyperplasia and the functional activation of human mast cells and melanocytes in vivo has implications for our understanding of the role of endogenous SCF in health and disease. These findings also indicate that the interaction between SCF and its receptor represents a potential therapeutic target for regulating the numbers and functional activity of both mast cells and cutaneous melanocytes.

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Increased mast cell number in human hypertensive nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.00374.2007 ◽

2008 ◽

Vol 295 (4) ◽

pp. F1103-F1109 ◽

Cited By ~ 19

Author(s):

Pia Welker ◽

Stephanie Krämer ◽

David A. Groneberg ◽

Hans H. Neumayer ◽

Sebastian Bachmann ◽

...

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Mast Cells ◽

Stem Cell Factor ◽

Early Stage ◽

Cell Number ◽

Blue Staining ◽

Cell Phenotype ◽

Hypertensive Nephropathy ◽

Mast Cell Number

Mast cells have recently been related to nonallergic chronic organ damage and fibrosis. In the present study, we analyzed mast cell number, localization, and maturation in the kidney of a relatively unique group of middle-aged accident victims with primary essential hypertension and in normotensive controls ( n = 8 per group, Caucasians, predominantly male). Hypertensive kidneys showed a significantly higher degree of arteriolosclerosis. However, glomerular and tubulointerstitial matrix accumulation did not differ significantly to normotensive controls indicating a relatively early stage of hypertensive nephropathy. Using toluidine blue staining, renal mast cell number was found to be fivefold higher in hypertensive subjects compared with normotensive controls. Mast cells were primarily located in the peritubular interstitial spaces, some perivascular, but not in glomeruli. In a series of immunohistological staining studies, mast cell maturation grading showed that expression of early hematopoietic precursor cell marker CD34 did not differ between both groups. In contrast, mast cells were mostly positive for IgE receptor, tryptase, and chymase indicating a mature, differentiated cell phenotype in hypertensive nephropathy. Renal expression of stem cell factor was markedly upregulated in primary hypertension. Kidney macrophage and lymphocyte numbers were similar in both groups. In conclusion, human hypertensive kidney disease shows an early and conspicuous upregulation of stem cell factor along with an increased number of mature mast cells. The results suggest that renal mast cell accumulation may play a role in the pathogenesis of human hypertensive nephropathy.

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Abstract 15720: Transmembrane Stem Cell Factor Delivered in Nanocarriers Promotes Angiogenesis in Ischemia Without Mast Cell Activation

Circulation ◽

10.1161/circ.142.suppl_3.15720 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Eri Takematsu ◽

Sanjana Srinath ◽

Michael Sherman ◽

Andrew K Dunn ◽

Aaron Baker

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Mast Cells ◽

Stem Cell Factor ◽

Cell Activation ◽

The Body ◽

Mast Cell Activation ◽

Protein Therapy ◽

Current Standard ◽

Therapeutic Benefits

Introduction: The current standard cares for peripheral artery disease (PAD) include surgical revascularizations with bypass grafting or percutaneous interventions. However, these interventions cannot be performed in a significant portion of patients, and many do not respond to these surgical procedures. Protein therapy to stimulate the body to create new vasculature is another alternative, which is minimally invasive to patients. Stem cell factor (SCF) is a candidate protein for treating PAD, but clinical use of SCF has been limited due to toxicity related to mast cell activation. SCF also exists in a transmembrane form (tmSCF), possessing differential activities from soluble SCF and has not been explored as a therapeutic agent. Results: To develop tmSCF as a therapeutic we created tmSCF embedded in liposome or lipid nanodisc (Fig. A) . Hindlimb ischemia model on WT and ob/ob mice showed that tmSCF proteliposome (tmSCFPL) and nanodisc (tmSCFND) improved blood flow recovery significantly more than control (Fig. B, C) . Mouse model of anaphylaxis revealed that tmSCF-based therapies did not activate mast cells (Fig. D, E) . Colocalization assay of c-Kit and clathrin/caveolin revealed that mast cells preferentially use clathrin-mediated pathways to internalize SCF and caveolin-mediated pathways for tmSCF-based therapies (Fig. F, G) . Surface c-Kit internalization study on mast cells showed faster uptake of SCF in comparison to tmSCF-based therapies (Fig. H) . Previous study indicates that clathrin-mediated internalization causes increased activation of mast cells. Our studies together with the previous finding suggest that mast cell activation does not occur for tmSCF-based therapies because of the slower uptake, greater utilization of the caveolin internalization pathway and weaker activation of mast cells. Conclusions: TmSCF-based therapies can provide therapeutic benefits without off-target effects on mast cells by tuning activation with nanocarriers.

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