Immunology Letters 159 (2014) 11–14
Contents lists available at ScienceDirect
Immunology Letters journal homepage: www.elsevier.com/locate/immlet
Review
Mast cell ontogeny: An historical overview Domenico Ribatti a,b,∗ , Enrico Crivellato c a
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy National Cancer Institute “Giovanni Paolo II”, Bari, Italy c Department of Experimental and Clinical Medicine, Section of Anatomy, Udine, Italy b
a r t i c l e
i n f o
Article history: Received 16 January 2014 Accepted 5 February 2014 Available online 14 February 2014 Keywords: Bone marrow c-kit Mast cells Ontogeny Stem cell factor
a b s t r a c t Mast cells were first identified by Paul Ehrlich in 1878, when he was still a medical student. Many fundamental aspects of mast cell ontogeny have been elucidated since Ehrlich’s first identification. Demonstration of mast cell derivation from bone marrow precursors could be established in 1977 when Kitamura’s group first showed reconstitution of mast cells in mast cell-deficient mice by the adaptive transfer of wild type bone marrow and indicated that these cells were of hematopoietic origin. It is now definitively established that development of mast cells in bone marrow occurs along the myeloid pathway. However, several aspects need further clarification. In particular, identification and chemical characterization of growth factors expressing mast cell differentiating properties and the relationship between mast cell and basophils developmental pathways. © 2014 Elsevier B.V. All rights reserved.
1. Introduction The traditional view is that mast cells arise from mast cell committed precursors in the bone marrow, circulate as agranular cells, then traverse the vascular space and enter the tissues or serosal cavity, where they complete their development, giving rise to specific subsets of mast cells with characteristic profiles of intracellular mediators at distinct sites within the body. They reside close to blood vessels, nerves, and mucosal surfaces, such as respiratory tract and gastrointestinal tract. Mast cells are absent in avascular tissues, including mineral bone, cartilage and cornea [1]. The history of the discovery of mast cell origin is complex and goes down to the early time when these cells were recognized by Ehrlich. It took many decades for scientist to elucidate the main aspects of mast cell ontogeny. Molecular biology and genetics have recently opened new field of research on this important research issue. 2. Early concepts on mast cell origin Mast cells were first identified by Paul Ehrlich (Fig. 1) in 1878, when he was still a medical student. In his doctoral dissertation,
∗ Corresponding author at: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico – Piazza G. Cesare, 11, 70124 Bari, Italy. Tel.: +39 080 5478326; fax: +39 080 5478310. E-mail address: [email protected] (D. Ribatti). http://dx.doi.org/10.1016/j.imlet.2014.02.003 0165-2478/© 2014 Elsevier B.V. All rights reserved.
whose title was “Beiträge zur Theorie und Praxis der histologischen Färbung” (“Contribution to the theory and practice of histological dyes”), Ehrlich described a class of aniline-positive cells of the connective tissues endowed with cytoplasmic metachromatic granules (“granulierte Bindgewebezellen”) for which he coined the name of “Mastzellen” [2]. He soon faced the issue of their origin. In his opinion, mast cells were connective cells which developed as a result of hyper nutrition. Thus, their aniline-positive metachromatic granules would represent deposits of nutrients. Being the functional role of the newly discovered cells mainly related to a “feeding” or “nourishing” activity, Ehrlich believed that they might derive from tissue pre-existing progenitors, suggesting that they differentiated from fibroblasts [3]. Later, Ehrlich regarded mast cells as “indices of the nutritional state of the connective tissue” [4]. Accordingly, it was feasible to find these cells accumulated in such over-nourished conditions as chronic inflammation, especially when it was aggravated by chronic lymphatic obstruction, and tumors. In successive memories, Ehrlich described the staining reactions of blood leukocytes on the basis of their specific affinities for various dyes [5,6]. He encountered cells with basophilic, metachromatic granules, and thus came to recognize two types of “Mastzellen”. The first, which could be identified and differentiated by its repertoire of coarse basophile granules ( granulation), lived in the connective tissues and apparently derived from them (tissue “Mastzell”). The second, the counterpart of the neutrophil polymorph and eosinophil leukocyte, contained basophilic granulation of the fine type (ı granulation), its origin was in the bone marrow and its habitat was in the peripheral blood (blood “Mastzell”, basophil or mast
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D. Ribatti, E. Crivellato / Immunology Letters 159 (2014) 11–14
Fig. 1. A portrait of P. Ehrlich.
leukocyte). By the time that his textbook of 1898 came to be revised [6], the evidence for the myeloid origin of the blood mast cells was complete [7]. Sixteen years after Ehrlich’s first description of Mastzellen, the English histologist and physiologist William Bate Hardy (Fig. 2) distinguished two types of granular basophile cells, i.e., the “coarsely granular basophile cells” and the “splanchnic basophile cells”, which both belonged to the population of “wandering cells” (the modern leukocytes) [8,9]. These tissue-homing cells corresponded to the subsets of connective tissue-type and mucosal mast cells, respectively, which would be described seventy years later by Enerbäck in rodents [10,11] (Fig. 3). Among the coarsely granular basophile cells, he also differentiated those cells which populated the serosal cavities – the so-called coelomic coarsely granular basophile cells – from the common coarsely granular basophile cells which were localized in the connective tissues. Hardy’s view of basophile cell function was partly in line with Ehrlich’s concept of a nutritional role for these cells. He believed that these cells might be somehow involved in the up-take and storage of substances as a result of hypernutrition. However, he also explored other experimental areas, such as the potential contribution of granular basophile cells to phagocytosis of pathogens and the participation of these cells to defence mechanisms during infections (for further historical data, see reference [12]). For several decades after Ehrlich’s discovery, the study of mast cell origin stood on pure conjectural bases being investigations supported by almost exclusively histological procedures. The scientific debate mainly focussed on the difference between mast cell and basophil developmental pathways. It was argued that mast cells and basophils, although very similar from a pure histological and histochemical ground, differed both in habitat and in parentage, at least in higher organisms. The derivation of mast cells was related
Fig. 2. A portrait of W. Bate Hardy.
Fig. 3. A typical elongated mast cell stained with an antibody anti-tryptase. Original magnification ×160.
D. Ribatti, E. Crivellato / Immunology Letters 159 (2014) 11–14
to fixed histiogenic elements whilst the origin of basophils was interpreted as deriving from the bone marrow. Michels wrote that “aside from an identical basophilic metachromatic reaction of the granules, the two cell types have nothing in common” [13]. 3. Hematopoietic origin of mast cells It was not until the end of the 1970s that scientists were able to solve the long-lasting enigma of the origin of mast cells. Demonstration of mast cell derivation from bone marrow precursors could be established in 1977 when Yukihiko Kitamura’s group first showed reconstitution of mast cells in mast cell-deficient mice by the adaptive transfer of wild type bone marrow and indicated that these cells were of hematopoietic origin [14,15].These Authors demonstrated the virtual absence of mast cells in W/Wv mice. Kitamura’s findings that transplantation of bone marrow cells from the congenic+/+ mice or from beige mice, whose mast cells can be identified because of their giant cytoplasmic granules, repaired the mast cell deficiency of the W/Wv mice provided clear evidence that mast cells derived from precursors that reside in the bone marrow. Moreover, these works showed that mutations at W had a more profound effect on the mast cell than on any other hematopoietic lineage. 4. The role played by c-kit and stem cell factor in mast cell differentiation Two groups reported that the W gene product encodes the ckit tyrosine kinase receptor [16,17]. Collectively, these mutations reduce signaling through c-kit to about 10% of normal level. C-kit is expressed on hematopoietic stem cells and is retained on mast cells throughout their development and differentiation but is downregulated during differentiation of other bone marrow-derived cells, including basophils. In contrast to mast cells, basophils reach their maturation in bone marrow before release into blood. Shortly after the discovery of c-kit, it was simultaneously reported that steel locus (sl) encodes the corresponding ligand, named kit ligand (KL) [18], mast cell growth factor (MGF) [19], steel factor (SLF or SF) [20], and stem cell factor (SCF) [21]. SCF is the main survival and developmental factor for mast cells, is produced mainly by murine and human fibroblasts, as well as by several other cell types, where is expressed on the cell surface or released in soluble form [18,19,22]. Injection of SCF into the skin of human being result in local accumulation of mast cells [23]. Furitsu et al. [24] found that monolayers of murine 3T3 fibroblasts or soluble factor derived from these cells could support human mast cell differentiation. These cells could be maintained in vitro for several months and had characteristics protease granule markers, tryptase and chymase [25]. SCF is primarily responsible for mast cell growth in human cord blood or fetal liver/3T3 fibroblast co-culture system [26,27]. The growth and differentiation of mast cells from unselected or CD34+ selected fetal liver or bone marrow cell populations is also controlled by SCF, although interleukin-3 (IL-3) play a supportive role [28,29]. Human mast cells grown in vitro from cord blood or fetal liver do not clearly proceed from tryptase containing mast cell (MCT/mucosal type) to tryptase–chymase containing mast cell (MCTC/serosal type) phenotypes; however, there appears to be a predominance of MCT cells in fetal liver and of MCTC in cord blood cultures. Differences in progenitor profiles of cord blood and fetal liver may predict in the presence of SCF, differences in mast cell phenotype commitment and differentiation in vitro [28]. When bone marrow mast cells from normal mice were transferred to mast cell-deficient mice, the cells retained their mucosal cell phenotype at tissue sites that normal bear this phenotype while adopted a serosal mast cell phenotype at sites that contain such cells [30].
13
Both serosal- and mucosal-type rat mast cells develop after in vivo treatment with SCF [31]. Jamur and colleagues [32] isolated a committed mast cell precursor in the bone marrow of adult Balb/c mice, characterized as CD34+ , CD13+ , c-kit+ , FCRI− , which gave rise to mast cells in vitro and reconstituted the mast cell population in lethally irradiated mice. 5. The role of interleukin-3 in mast cells differentiation In 1983, Ihle and collaborators [33] demonstrated that IL-3 promoted the growth of mast cells from mouse bone marrow. Rat mucosal mast cell phenotype in vitro is regulated by SCF interacting with c-kit while IL-3 may enhance phenotype switch into a serosal mast cell [34]. IL-3 is not required for the development of human cord-blood derived mast cells in the presence of low oxygen concentration [35]. However, IL-3 can enhance SCF-dependent mast cell development at low cell densities at normal oxygen concentration [36]. Nerve growth factor promotes differentiation and proliferation of mouse bone marrow mast cells in the presence of IL-3 [37]. A mast cell committed precursor characterized by a THY1low KIThi mMCP2 (mast cell protease-2, also known as MCPT2)+ mMCP4 (also known as MCP4)+ CPA3+ phenotype was identified in the fetal blood at day 15.5 of gestation [38]. These cells gave rise to pure colonies of mast cells upon culturing with IL-3 and SCF. Intravenous adaptive transfer of these cells into W/Wv mice reconstituted the mast cell population in the peritoneal cavity of the host, providing the proof that mast cell precursors traffic to the tissue and differentiate. 6. Differentiation of mast cells along the myeloid pathway Development of mast cells in mouse bone marrow occurs along the myeloid pathway. The common myeloid progenitor (CMP) can give rise to either the magakaryocyte-erythrocyte progenitor or to the granulocyte macrophage progenitor (GMP). The GMP can give rise to macrophages, eosinophils, neutrophils or to basophil-mast cell progenitor (BMCP). BMCP could be identified as a KIT+ , FC␥ RII/RIII+ , 7 integrinhi , FCRI− cell that only give rise to mast cells or basophils in culture and transfer of BMCP into mast cell deficient mice led to the appearance of mast cells in the spleen and peritoneal cavity [39]. Accordingly to a different model of differentiation, a mast cell progenitor FCRI− CD27− 7 integrin+ , IL33R+ was able to restore mast cell but not other lineages after transfer into mast cell deficient mice [40]. The expression of integrin heterodimer ␣4 7 on mast cells and the corresponding ligands vascular cell adhesion molecule-1 (VCAM-1) or mucosal addressin cell adhesion molecule-1 (MadCAM-1) on the intestine was critical for constitutive homing and maintenance of a pool of mast cell progenitors in the intestine [41]. Directed migration by chemokine receptors and their ligands influence the localization of mast cell progenitors. CXCR-2 is critical for the constitutive localization of mast cell progenitors to the intestine [42]. It was also proposed that mast cells develop from a granulocyte/monocyte progenitor cell, and that their lineage specification is regulated by the timed expression of the transcription factors GATA-binding protein 2 (GATA2) and CCAAT/enhancer-binding protein alpha (C/EBP␣) [43]. 7. Conclusions Many fundamental aspects of mast cell ontogeny have been elucidated since Ehrlich’s first identification. The discovery that mast cells have their origin in the bone marrow and develop along the
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myeloid pathway represented a basic achievement in the process of understanding mast cell biological profile. This origin is part of the tunable and adaptive character of mast cell function. Many aspects need further clarification. In particular, identification and chemical characterization of growth factors expressing mast cell differentiating properties and the intricate relationship between mast cell and basophils developmental pathways deserve further investigation. In a pharmacological perspective, these studies will hopefully shed new light on molecular strategies aimed at modulating mast cell development and activity. References [1] Crivellato E, Beltrami CA, Mallardi F, Ribatti D. The mast cell: an active participant or an innocent bystander. Histology and Histopathology 2004;19: 259–70. [2] Ehrlich P. Beiträge zur Theorie und Praxis der histologischen Färbung. Leipzig University; 1878. [3] Crivellato E, Beltrami C, Mallardi F, Ribatti D. Paul Ehrlich’s doctoral thesis: a milestone in the study of mast cells. British Journal of Haematology 2003;123:19–21. [4] Ehrlich P. Beiträge zur Kenntnis der granulierten Bindgewebenzellen und der eosinophilen Leukocyten. Archiv für Anatomie und Physiologie 1879;3:166–9. [5] Ehrlich P. Farbenanalytische Untersuchungen zur Histologie und Klinik des Blutes. Hirschwald: Berlin; 1891. [6] Ehrlich P, Lazarus A. Die Anemie. 1. Normale und Patologische Histologie des Blutes. Wien: Holder; 1898 (revised and republished 1909). [7] Jolly M. Clasmatocytes et mastzellen. Compte Rendus Société de Biologie (Paris) 1900;52:437–55. [8] Kanthack AA, Hardy WB. The morphology and distribution of the wandering cells of Mammalia. Journal of Physiology 1894;17. p. 80, 81–119. [9] Hardy WB, Wesbrook FF. The wandering cells of the alimentary canal. Journal of Physiology 1895;18:490–3. [10] Enerback L. Mast cells in rat gastrointestinal mucosa. I. Effects of fixation. Acta Pathologica et Microbiologica Scandinavica 1966;66:289–302. [11] Enerback L. Mast cells in rat gastrointestinal mucosa. 2. Dye-binding and metachromatic properties. Acta Pathologica et Microbiologica Scandinavica 1966;66:303–12. [12] Crivellato E, Ribatti D. The fundamental contribution of William Bate Hardy to shape the concept of mast cell heterogeneity. British Journal of Haematology 2010;150:152–7. [13] Michels N. The mast cells. In: Downey H, editor. Handbook of hematology, vol. 1. New York: Hoeber; 1938. p. 232–354. [14] Kitamura Y, Shimada M, Hatanaka K, Miyano Y. Development of mast cells from grafted bone marrow cells in irradiated mice. Nature 1977;268:442–3. [15] Kitamura Y, Go S, Hatanaka K. Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 1978;52:447–52. [16] Chabot B, Stephenson DA, Chapman VM, Besmer P, Bernstein A. The protooncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature 1988;335:88–9. [17] Geissler EN, Ryan MA, Housman DE. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell 1988;55:185–92. [18] Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW, et al. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 1990;63:225–33. [19] Anderson DM, Lyman SD, Baird A, Wignall JM, Eisenman J, Rauch C, et al. Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell 1990;63:235–43. [20] Witte ON. Steel locus defines new multipotent growth factor. Cell 1990;63:5–6. [21] Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, et al. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 1990;63:213–24. [22] Williams DE, Eisenman J, Baird A, Rauch C, Van Ness K, March CJ, et al. Identification of a ligand for the c-kit proto-oncogene. Cell 1990;63:167–74. [23] Costa JJ, Demetri GD, Harrist TJ, Dvorak AM, Hayes DF, Merica EA, et al. Recombinant human stem cell factor (kit ligand) promotes human mast cell and
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Contents lists available at ScienceDirect
Immunology Letters journal homepage: www.elsevier.com/locate/immlet
Review
Mast cell ontogeny: An historical overview Domenico Ribatti a,b,∗ , Enrico Crivellato c a
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy National Cancer Institute “Giovanni Paolo II”, Bari, Italy c Department of Experimental and Clinical Medicine, Section of Anatomy, Udine, Italy b
a r t i c l e
i n f o
Article history: Received 16 January 2014 Accepted 5 February 2014 Available online 14 February 2014 Keywords: Bone marrow c-kit Mast cells Ontogeny Stem cell factor
a b s t r a c t Mast cells were first identified by Paul Ehrlich in 1878, when he was still a medical student. Many fundamental aspects of mast cell ontogeny have been elucidated since Ehrlich’s first identification. Demonstration of mast cell derivation from bone marrow precursors could be established in 1977 when Kitamura’s group first showed reconstitution of mast cells in mast cell-deficient mice by the adaptive transfer of wild type bone marrow and indicated that these cells were of hematopoietic origin. It is now definitively established that development of mast cells in bone marrow occurs along the myeloid pathway. However, several aspects need further clarification. In particular, identification and chemical characterization of growth factors expressing mast cell differentiating properties and the relationship between mast cell and basophils developmental pathways. © 2014 Elsevier B.V. All rights reserved.
1. Introduction The traditional view is that mast cells arise from mast cell committed precursors in the bone marrow, circulate as agranular cells, then traverse the vascular space and enter the tissues or serosal cavity, where they complete their development, giving rise to specific subsets of mast cells with characteristic profiles of intracellular mediators at distinct sites within the body. They reside close to blood vessels, nerves, and mucosal surfaces, such as respiratory tract and gastrointestinal tract. Mast cells are absent in avascular tissues, including mineral bone, cartilage and cornea [1]. The history of the discovery of mast cell origin is complex and goes down to the early time when these cells were recognized by Ehrlich. It took many decades for scientist to elucidate the main aspects of mast cell ontogeny. Molecular biology and genetics have recently opened new field of research on this important research issue. 2. Early concepts on mast cell origin Mast cells were first identified by Paul Ehrlich (Fig. 1) in 1878, when he was still a medical student. In his doctoral dissertation,
∗ Corresponding author at: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico – Piazza G. Cesare, 11, 70124 Bari, Italy. Tel.: +39 080 5478326; fax: +39 080 5478310. E-mail address: [email protected] (D. Ribatti). http://dx.doi.org/10.1016/j.imlet.2014.02.003 0165-2478/© 2014 Elsevier B.V. All rights reserved.
whose title was “Beiträge zur Theorie und Praxis der histologischen Färbung” (“Contribution to the theory and practice of histological dyes”), Ehrlich described a class of aniline-positive cells of the connective tissues endowed with cytoplasmic metachromatic granules (“granulierte Bindgewebezellen”) for which he coined the name of “Mastzellen” [2]. He soon faced the issue of their origin. In his opinion, mast cells were connective cells which developed as a result of hyper nutrition. Thus, their aniline-positive metachromatic granules would represent deposits of nutrients. Being the functional role of the newly discovered cells mainly related to a “feeding” or “nourishing” activity, Ehrlich believed that they might derive from tissue pre-existing progenitors, suggesting that they differentiated from fibroblasts [3]. Later, Ehrlich regarded mast cells as “indices of the nutritional state of the connective tissue” [4]. Accordingly, it was feasible to find these cells accumulated in such over-nourished conditions as chronic inflammation, especially when it was aggravated by chronic lymphatic obstruction, and tumors. In successive memories, Ehrlich described the staining reactions of blood leukocytes on the basis of their specific affinities for various dyes [5,6]. He encountered cells with basophilic, metachromatic granules, and thus came to recognize two types of “Mastzellen”. The first, which could be identified and differentiated by its repertoire of coarse basophile granules ( granulation), lived in the connective tissues and apparently derived from them (tissue “Mastzell”). The second, the counterpart of the neutrophil polymorph and eosinophil leukocyte, contained basophilic granulation of the fine type (ı granulation), its origin was in the bone marrow and its habitat was in the peripheral blood (blood “Mastzell”, basophil or mast
12
D. Ribatti, E. Crivellato / Immunology Letters 159 (2014) 11–14
Fig. 1. A portrait of P. Ehrlich.
leukocyte). By the time that his textbook of 1898 came to be revised [6], the evidence for the myeloid origin of the blood mast cells was complete [7]. Sixteen years after Ehrlich’s first description of Mastzellen, the English histologist and physiologist William Bate Hardy (Fig. 2) distinguished two types of granular basophile cells, i.e., the “coarsely granular basophile cells” and the “splanchnic basophile cells”, which both belonged to the population of “wandering cells” (the modern leukocytes) [8,9]. These tissue-homing cells corresponded to the subsets of connective tissue-type and mucosal mast cells, respectively, which would be described seventy years later by Enerbäck in rodents [10,11] (Fig. 3). Among the coarsely granular basophile cells, he also differentiated those cells which populated the serosal cavities – the so-called coelomic coarsely granular basophile cells – from the common coarsely granular basophile cells which were localized in the connective tissues. Hardy’s view of basophile cell function was partly in line with Ehrlich’s concept of a nutritional role for these cells. He believed that these cells might be somehow involved in the up-take and storage of substances as a result of hypernutrition. However, he also explored other experimental areas, such as the potential contribution of granular basophile cells to phagocytosis of pathogens and the participation of these cells to defence mechanisms during infections (for further historical data, see reference [12]). For several decades after Ehrlich’s discovery, the study of mast cell origin stood on pure conjectural bases being investigations supported by almost exclusively histological procedures. The scientific debate mainly focussed on the difference between mast cell and basophil developmental pathways. It was argued that mast cells and basophils, although very similar from a pure histological and histochemical ground, differed both in habitat and in parentage, at least in higher organisms. The derivation of mast cells was related
Fig. 2. A portrait of W. Bate Hardy.
Fig. 3. A typical elongated mast cell stained with an antibody anti-tryptase. Original magnification ×160.
D. Ribatti, E. Crivellato / Immunology Letters 159 (2014) 11–14
to fixed histiogenic elements whilst the origin of basophils was interpreted as deriving from the bone marrow. Michels wrote that “aside from an identical basophilic metachromatic reaction of the granules, the two cell types have nothing in common” [13]. 3. Hematopoietic origin of mast cells It was not until the end of the 1970s that scientists were able to solve the long-lasting enigma of the origin of mast cells. Demonstration of mast cell derivation from bone marrow precursors could be established in 1977 when Yukihiko Kitamura’s group first showed reconstitution of mast cells in mast cell-deficient mice by the adaptive transfer of wild type bone marrow and indicated that these cells were of hematopoietic origin [14,15].These Authors demonstrated the virtual absence of mast cells in W/Wv mice. Kitamura’s findings that transplantation of bone marrow cells from the congenic+/+ mice or from beige mice, whose mast cells can be identified because of their giant cytoplasmic granules, repaired the mast cell deficiency of the W/Wv mice provided clear evidence that mast cells derived from precursors that reside in the bone marrow. Moreover, these works showed that mutations at W had a more profound effect on the mast cell than on any other hematopoietic lineage. 4. The role played by c-kit and stem cell factor in mast cell differentiation Two groups reported that the W gene product encodes the ckit tyrosine kinase receptor [16,17]. Collectively, these mutations reduce signaling through c-kit to about 10% of normal level. C-kit is expressed on hematopoietic stem cells and is retained on mast cells throughout their development and differentiation but is downregulated during differentiation of other bone marrow-derived cells, including basophils. In contrast to mast cells, basophils reach their maturation in bone marrow before release into blood. Shortly after the discovery of c-kit, it was simultaneously reported that steel locus (sl) encodes the corresponding ligand, named kit ligand (KL) [18], mast cell growth factor (MGF) [19], steel factor (SLF or SF) [20], and stem cell factor (SCF) [21]. SCF is the main survival and developmental factor for mast cells, is produced mainly by murine and human fibroblasts, as well as by several other cell types, where is expressed on the cell surface or released in soluble form [18,19,22]. Injection of SCF into the skin of human being result in local accumulation of mast cells [23]. Furitsu et al. [24] found that monolayers of murine 3T3 fibroblasts or soluble factor derived from these cells could support human mast cell differentiation. These cells could be maintained in vitro for several months and had characteristics protease granule markers, tryptase and chymase [25]. SCF is primarily responsible for mast cell growth in human cord blood or fetal liver/3T3 fibroblast co-culture system [26,27]. The growth and differentiation of mast cells from unselected or CD34+ selected fetal liver or bone marrow cell populations is also controlled by SCF, although interleukin-3 (IL-3) play a supportive role [28,29]. Human mast cells grown in vitro from cord blood or fetal liver do not clearly proceed from tryptase containing mast cell (MCT/mucosal type) to tryptase–chymase containing mast cell (MCTC/serosal type) phenotypes; however, there appears to be a predominance of MCT cells in fetal liver and of MCTC in cord blood cultures. Differences in progenitor profiles of cord blood and fetal liver may predict in the presence of SCF, differences in mast cell phenotype commitment and differentiation in vitro [28]. When bone marrow mast cells from normal mice were transferred to mast cell-deficient mice, the cells retained their mucosal cell phenotype at tissue sites that normal bear this phenotype while adopted a serosal mast cell phenotype at sites that contain such cells [30].
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Both serosal- and mucosal-type rat mast cells develop after in vivo treatment with SCF [31]. Jamur and colleagues [32] isolated a committed mast cell precursor in the bone marrow of adult Balb/c mice, characterized as CD34+ , CD13+ , c-kit+ , FCRI− , which gave rise to mast cells in vitro and reconstituted the mast cell population in lethally irradiated mice. 5. The role of interleukin-3 in mast cells differentiation In 1983, Ihle and collaborators [33] demonstrated that IL-3 promoted the growth of mast cells from mouse bone marrow. Rat mucosal mast cell phenotype in vitro is regulated by SCF interacting with c-kit while IL-3 may enhance phenotype switch into a serosal mast cell [34]. IL-3 is not required for the development of human cord-blood derived mast cells in the presence of low oxygen concentration [35]. However, IL-3 can enhance SCF-dependent mast cell development at low cell densities at normal oxygen concentration [36]. Nerve growth factor promotes differentiation and proliferation of mouse bone marrow mast cells in the presence of IL-3 [37]. A mast cell committed precursor characterized by a THY1low KIThi mMCP2 (mast cell protease-2, also known as MCPT2)+ mMCP4 (also known as MCP4)+ CPA3+ phenotype was identified in the fetal blood at day 15.5 of gestation [38]. These cells gave rise to pure colonies of mast cells upon culturing with IL-3 and SCF. Intravenous adaptive transfer of these cells into W/Wv mice reconstituted the mast cell population in the peritoneal cavity of the host, providing the proof that mast cell precursors traffic to the tissue and differentiate. 6. Differentiation of mast cells along the myeloid pathway Development of mast cells in mouse bone marrow occurs along the myeloid pathway. The common myeloid progenitor (CMP) can give rise to either the magakaryocyte-erythrocyte progenitor or to the granulocyte macrophage progenitor (GMP). The GMP can give rise to macrophages, eosinophils, neutrophils or to basophil-mast cell progenitor (BMCP). BMCP could be identified as a KIT+ , FC␥ RII/RIII+ , 7 integrinhi , FCRI− cell that only give rise to mast cells or basophils in culture and transfer of BMCP into mast cell deficient mice led to the appearance of mast cells in the spleen and peritoneal cavity [39]. Accordingly to a different model of differentiation, a mast cell progenitor FCRI− CD27− 7 integrin+ , IL33R+ was able to restore mast cell but not other lineages after transfer into mast cell deficient mice [40]. The expression of integrin heterodimer ␣4 7 on mast cells and the corresponding ligands vascular cell adhesion molecule-1 (VCAM-1) or mucosal addressin cell adhesion molecule-1 (MadCAM-1) on the intestine was critical for constitutive homing and maintenance of a pool of mast cell progenitors in the intestine [41]. Directed migration by chemokine receptors and their ligands influence the localization of mast cell progenitors. CXCR-2 is critical for the constitutive localization of mast cell progenitors to the intestine [42]. It was also proposed that mast cells develop from a granulocyte/monocyte progenitor cell, and that their lineage specification is regulated by the timed expression of the transcription factors GATA-binding protein 2 (GATA2) and CCAAT/enhancer-binding protein alpha (C/EBP␣) [43]. 7. Conclusions Many fundamental aspects of mast cell ontogeny have been elucidated since Ehrlich’s first identification. The discovery that mast cells have their origin in the bone marrow and develop along the
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myeloid pathway represented a basic achievement in the process of understanding mast cell biological profile. This origin is part of the tunable and adaptive character of mast cell function. Many aspects need further clarification. In particular, identification and chemical characterization of growth factors expressing mast cell differentiating properties and the intricate relationship between mast cell and basophils developmental pathways deserve further investigation. In a pharmacological perspective, these studies will hopefully shed new light on molecular strategies aimed at modulating mast cell development and activity. References [1] Crivellato E, Beltrami CA, Mallardi F, Ribatti D. The mast cell: an active participant or an innocent bystander. Histology and Histopathology 2004;19: 259–70. [2] Ehrlich P. Beiträge zur Theorie und Praxis der histologischen Färbung. Leipzig University; 1878. [3] Crivellato E, Beltrami C, Mallardi F, Ribatti D. Paul Ehrlich’s doctoral thesis: a milestone in the study of mast cells. British Journal of Haematology 2003;123:19–21. [4] Ehrlich P. Beiträge zur Kenntnis der granulierten Bindgewebenzellen und der eosinophilen Leukocyten. Archiv für Anatomie und Physiologie 1879;3:166–9. [5] Ehrlich P. Farbenanalytische Untersuchungen zur Histologie und Klinik des Blutes. Hirschwald: Berlin; 1891. [6] Ehrlich P, Lazarus A. Die Anemie. 1. Normale und Patologische Histologie des Blutes. Wien: Holder; 1898 (revised and republished 1909). [7] Jolly M. Clasmatocytes et mastzellen. Compte Rendus Société de Biologie (Paris) 1900;52:437–55. [8] Kanthack AA, Hardy WB. The morphology and distribution of the wandering cells of Mammalia. Journal of Physiology 1894;17. p. 80, 81–119. [9] Hardy WB, Wesbrook FF. The wandering cells of the alimentary canal. Journal of Physiology 1895;18:490–3. [10] Enerback L. Mast cells in rat gastrointestinal mucosa. I. Effects of fixation. Acta Pathologica et Microbiologica Scandinavica 1966;66:289–302. [11] Enerback L. Mast cells in rat gastrointestinal mucosa. 2. Dye-binding and metachromatic properties. Acta Pathologica et Microbiologica Scandinavica 1966;66:303–12. [12] Crivellato E, Ribatti D. The fundamental contribution of William Bate Hardy to shape the concept of mast cell heterogeneity. British Journal of Haematology 2010;150:152–7. [13] Michels N. The mast cells. In: Downey H, editor. Handbook of hematology, vol. 1. New York: Hoeber; 1938. p. 232–354. [14] Kitamura Y, Shimada M, Hatanaka K, Miyano Y. Development of mast cells from grafted bone marrow cells in irradiated mice. Nature 1977;268:442–3. [15] Kitamura Y, Go S, Hatanaka K. Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 1978;52:447–52. [16] Chabot B, Stephenson DA, Chapman VM, Besmer P, Bernstein A. The protooncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature 1988;335:88–9. [17] Geissler EN, Ryan MA, Housman DE. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell 1988;55:185–92. [18] Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW, et al. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 1990;63:225–33. [19] Anderson DM, Lyman SD, Baird A, Wignall JM, Eisenman J, Rauch C, et al. Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell 1990;63:235–43. [20] Witte ON. Steel locus defines new multipotent growth factor. Cell 1990;63:5–6. [21] Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, et al. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 1990;63:213–24. [22] Williams DE, Eisenman J, Baird A, Rauch C, Van Ness K, March CJ, et al. Identification of a ligand for the c-kit proto-oncogene. Cell 1990;63:167–74. [23] Costa JJ, Demetri GD, Harrist TJ, Dvorak AM, Hayes DF, Merica EA, et al. Recombinant human stem cell factor (kit ligand) promotes human mast cell and
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