*1.1. Mast Cell Development*

Mast cells (MCs) are hematopoietic cells of the myeloid lineage [1]. They can be found particularly in tissues with close contact to the environment, such as skin, gastrointestinal tract, upper airways, and lung [2]. However, MCs are also located in other vascularized organs (e.g., liver and kidney [3,4]). Correlating with their presence in various locations, MCs present as a highly heterogeneous cell population with subtype-dependent differences in cell morphology, histochemical properties, expression of granular proteases, and function, amongst others [5]. This intriguing plasticity and heterogeneity also have their origin in the differentiation process of MCs [6].

MCs originate from hematopoietic stem cells, which differentiate into MC precursors (MCps) in the bone marrow. MCps then leave the bone marrow and distribute via the blood and transendothelial migration into target tissues, where they eventually phenotypically mature in the presence of tissue-specific factors, such as cytokines, growth factors, and extracellular matrix (ECM) components. Different maturation conditions lead to functionally diverse MCs, which can be subdivided in mice in chymase-expressing mucosa-type MCs (MMCs) and tryptase/chymase-expressing connective tissue-type MCs (CTMCs).

From a signaling perspective, MC development in vivo is strictly dependent on the expression of the receptor tyrosine kinase KIT, also known as CD117 [7]. Likewise, expression of the KIT ligand stem cell factor (SCF) is mandatory for MC development in vivo [8]. Another prominent MC receptor is the high-affinity receptor for IgE (FcεRI) [9], which is important, amongst other factors, for defense against helminths, but also for the induction of allergic reactions. The co-expression of both KIT and FcεRI, in addition to distinct cytoplasmic metachromatic granules (also termed secretory lysosomes), characterizes mature MCs [2].

With respect to the distribution of MCps through the blood to respective target tissues, productive interactions between surface molecules of MCps and endothelial cells are required for transendothelial migration [10]. As an example, the homing of MCps to the small intestine is dependent on the α4β7 integrin on the MCps, and MAdCAM-1 and VCAM1 as counterligands on the endothelial cells [11]. For α4β7 integrin activation by inside-out signaling, ligand-induced activation of CXCR2 on MCps is required [12]. After migration to the different tissues, MCps differentiate into tissue-specific mature MCs, which can belong to either of the two major subclasses of MCs, MMCs or CTMCs. In addition to the subtype- and tissue-specific changes in secretory potential (e.g., differential content of secretory lysosomes and configuration of signaling systems), mature MCs downregulate cell-surface adhesion molecules and chemokine receptors [13,14]. Intriguingly, by using a new fate mapping mouse model, Gentek et al. recently demonstrated that MCs have dual developmental origins [15]. Whereas most skin MCs are of primitive origin during embryogenesis (i.e., yolk sac derived), adult definitive MCs originate from definitive hematopoietic stem cells of the aorta-gonad-mesonephros vascular endothelium. Moreover, in this study it was demonstrated that replenishment of adult tissue MCs predominantly occurs via the proliferation/differentiation of long-lived tissue-resident precursors [15]. These data were in principle verified by Li et al. [16]. However, by applying two different fate mapping mouse models, they could demonstrate that most CTMCs even derive from late erythro-myeloid progenitors generated at the hemogenic endothelium of the yolk sac.
