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• W2897650637 abstract "•Three waves of fetal hematopoiesis contribute to fetal mast cells in succession•The three origin-derived mast cells have distinct tissue preferences•Integrin β7+CD117+CD11blow cells are embryonic mast cell precursors•Late EMP-derived mast cells are the major composition of adult CTMCs Tissue-resident mast cells are associated with many inflammatory and physiological processes. Although mast cells arise from the yolk sac, the exact ontogeny of adult mast cells remains unclear. Here we have investigated the hematopoietic origin of mast cells using fate-mapping systems. We have shown that early erythro-myeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells (HSCs) each gave rise to mast cells in succession via an intermediate integrin β7+ progenitor. From late embryogenesis to adult, early EMP-derived mast cells were largely replaced by late EMP-derived cells in most connective tissues except adipose and pleural cavity. Thus, mast cells with distinct origin displayed tissue-location preferences: early EMP-derived cells were limited to adipose and pleural cavity and late EMP-derived cells dominated most connective tissues, while HSC-derived cells were a main group in mucosa. Therefore, embryonic origin shapes the heterogeneity of adult mast cells, with diverse functions in immunity and development. Tissue-resident mast cells are associated with many inflammatory and physiological processes. Although mast cells arise from the yolk sac, the exact ontogeny of adult mast cells remains unclear. Here we have investigated the hematopoietic origin of mast cells using fate-mapping systems. We have shown that early erythro-myeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells (HSCs) each gave rise to mast cells in succession via an intermediate integrin β7+ progenitor. From late embryogenesis to adult, early EMP-derived mast cells were largely replaced by late EMP-derived cells in most connective tissues except adipose and pleural cavity. Thus, mast cells with distinct origin displayed tissue-location preferences: early EMP-derived cells were limited to adipose and pleural cavity and late EMP-derived cells dominated most connective tissues, while HSC-derived cells were a main group in mucosa. Therefore, embryonic origin shapes the heterogeneity of adult mast cells, with diverse functions in immunity and development. Mast cells are key effectors of type I allergic responses and also are proposed to participate in a wider variety of physiological and pathological processes including organ development (Lilla and Werb, 2010Lilla J.N. Werb Z. Mast cells contribute to the stromal microenvironment in mammary gland branching morphogenesis.Dev. Biol. 2010; 337: 124-133Crossref PubMed Scopus (77) Google Scholar, Liu et al., 2015Liu J. Fu T. Song F. Xue Y. Xia C. Liu P. Wang H. Zhong J. Li Q. Chen J. et al.Mast Cells Participate in Corneal Development in Mice.Sci. Rep. 2015; 5: 17569Crossref PubMed Scopus (36) Google Scholar), skin-barrier homeostasis (Kurashima et al., 2014Kurashima Y. Amiya T. Fujisawa K. Shibata N. Suzuki Y. Kogure Y. Hashimoto E. Otsuka A. Kabashima K. Sato S. et al.The enzyme Cyp26b1 mediates inhibition of mast cell activation by fibroblasts to maintain skin-barrier homeostasis.Immunity. 2014; 40: 530-541Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar), wound healing (Douaiher et al., 2014Douaiher J. Succar J. Lancerotto L. Gurish M.F. Orgill D.P. Hamilton M.J. Krilis S.A. Stevens R.L. Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing.Adv. Immunol. 2014; 122: 211-252Crossref PubMed Scopus (106) Google Scholar), heart function (Ngkelo et al., 2016Ngkelo A. Richart A. Kirk J.A. Bonnin P. Vilar J. Lemitre M. Marck P. Branchereau M. Le Gall S. Renault N. et al.Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction.J. Exp. Med. 2016; 213: 1353-1374Crossref PubMed Scopus (71) Google Scholar), and tumor progression (da Silva et al., 2014da Silva E.Z. Jamur M.C. Oliver C. Mast cell function: a new vision of an old cell.J. Histochem. Cytochem. 2014; 62: 698-738Crossref PubMed Scopus (375) Google Scholar, Giannou et al., 2015Giannou A.D. Marazioti A. Spella M. Kanellakis N.I. Apostolopoulou H. Psallidas I. Prijovich Z.M. Vreka M. Zazara D.E. Lilis I. et al.Mast cells mediate malignant pleural effusion formation.J. Clin. Invest. 2015; 125: 2317-2334Crossref PubMed Scopus (69) Google Scholar). However, these functions of mast cells are still under debate, because most in vivo studies are based on Kit mutant mouse models that are deficient beyond the mast cell compartment. So, the exact physiological and pathogenic functions of mast cells need to be further studied. Mast cells predominantly reside in tissues and are subclassified into two main subsets based on their tissue distribution: connective tissue mast cells (CTMCs) are located around venules and nerve endings in most connective tissues (i.e., skin, tongue, trachea, esophagus, adipose, peritoneal cavity, and pleural cavity) and mucosal mast cells (MMCs) are located inside the epithelia of the gut and respiratory mucosa. Both CTMCs and MMCs are heterogeneous based on the distinct nature of their intracellular secretory granule proteases (i.e., chymases, tryptases, and carboxypeptidase). MMCs are inducible and transient with a lifespan of only 2 weeks, whereas CTMCs are constitutive and long-lasting (Dwyer et al., 2016Dwyer D.F. Barrett N.A. Austen K.F. Immunological Genome Project ConsortiumExpression profiling of constitutive mast cells reveals a unique identity within the immune system.Nat. Immunol. 2016; 17: 878-887Crossref PubMed Scopus (219) Google Scholar, Gurish and Austen, 2012Gurish M.F. Austen K.F. Developmental origin and functional specialization of mast cell subsets.Immunity. 2012; 37: 25-33Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). Both development-associated intrinsic factors and external factors in the tissue microenvironment are thought to corporate to shape the properties of these cell subtypes. Therefore, clarification of the origin and developmental route of mast cells is critical for understanding the heterogeneity of mast cells across tissues and thereby their biological functions. In 1978, Yukihiko Kitamura et al. showed that mast cells can be reconstituted in mast cell-deficient mice by the adoptive transfer of wild-type (WT) bone marrow cells, indicating that mast cells originate from bone marrow (BM). However, they also observed that the mast cell numbers in the skin, unlike the cell numbers in caecum, did not reach the same amounts as in the congenic control WT strain, even 105 days after transfer (Kitamura et al., 1978Kitamura Y. Go S. Hatanaka K. Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation.Blood. 1978; 52: 447-452Crossref PubMed Google Scholar). Thus, BM-derived mast cell progenitors (MCPs) cannot completely reconstitute the mast cell pool in the skin. Similarly, reconstitution assays in adult WT mice illustrate that, unlike MMCs, mast cells in the skin are only partially replaced by donor mast cells. This suggests that their maintenance during adulthood is independent of postnatal hematopoietic stem cells (HSCs) (Kitamura et al., 1977Kitamura Y. Shimada M. Hatanaka K. Miyano Y. Development of mast cells from grafted bone marrow cells in irradiated mice.Nature. 1977; 268: 442-443Crossref PubMed Scopus (236) Google Scholar). Whether this also applies to mast cells in other connective tissues and how the adult CTMC pool is maintained are both unknown. There are three hematopoietic “waves” during mouse embryogenesis. Primitive hematopoiesis appears in the extra-embryonic yolk sac at around embryonic day 7.25 (E7.25) and generates early erythro-myeloid progenitors (early EMPs). Then the second transient definitive wave of fetal hematopoiesis, spanning from E8 to E9.5, sequentially generates multi-lineage c-Myb+EMPs (also late EMPs) at the hemogenic endothelium of the yolk sac followed by c-Kit+lympho-myeloid progenitors (LMPs) at the intra-embryonic mesoderm. Finally, the definitive hematopoietic wave generating c-Kit+Sca-1+HSCs with long-term reconstitution activity emerges from E9.5 to E10.5 within the aorta, gonads, and mesonephros region (AGM). Fate-mapping technologies have allowed investigators to trace the contributions of these three hematopoietic waves to adult hematopoietic cells (Hoeffel and Ginhoux, 2015Hoeffel G. Ginhoux F. Ontogeny of Tissue-Resident Macrophages.Front. Immunol. 2015; 6: 486Crossref PubMed Scopus (198) Google Scholar, Kierdorf et al., 2015Kierdorf K. Prinz M. Geissmann F. Gomez Perdiguero E. Development and function of tissue resident macrophages in mice.Semin. Immunol. 2015; 27: 369-378Crossref PubMed Scopus (59) Google Scholar, McGrath et al., 2015McGrath K.E. Frame J.M. Palis J. Early hematopoiesis and macrophage development.Semin. Immunol. 2015; 27: 379-387Crossref PubMed Scopus (87) Google Scholar). For example, it has been shown recently that most tissue-resident macrophages originate from late EMPs, independently of adult HSCs, and are endowed with long-lasting self-renewing activities after birth (Ginhoux and Guilliams, 2016Ginhoux F. Guilliams M. Tissue-Resident Macrophage Ontogeny and Homeostasis.Immunity. 2016; 44: 439-449Abstract Full Text Full Text PDF PubMed Scopus (925) Google Scholar, Gomez Perdiguero et al., 2015Gomez Perdiguero E. Klapproth K. Schulz C. Busch K. Azzoni E. Crozet L. Garner H. Trouillet C. de Bruijn M.F. Geissmann F. Rodewald H.R. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors.Nature. 2015; 518: 547-551Crossref PubMed Scopus (1336) Google Scholar, Hoeffel et al., 2015Hoeffel G. Chen J. Lavin Y. Low D. Almeida F.F. See P. Beaudin A.E. Lum J. Low I. Forsberg E.C. et al.C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages.Immunity. 2015; 42: 665-678Abstract Full Text Full Text PDF PubMed Scopus (665) Google Scholar, Mass et al., 2016Mass E. Ballesteros I. Farlik M. Halbritter F. Günther P. Crozet L. Jacome-Galarza C.E. Händler K. Klughammer J. Kobayashi Y. et al.Specification of tissue-resident macrophages during organogenesis.Science. 2016; 353: aaf4238Crossref PubMed Scopus (468) Google Scholar). Tissue-resident macrophages and skin mast cells share many homeostatic properties such as radio-resistance and self-renewal. We thus wondered whether they might follow a similar embryonic origin and developmental route. Using limiting dilution assays in vivo, early studies reveal that embryonic precursors of mast cells appear in the yolk sac as early as E9.5, in the fetal liver at E11, and in the embryonic skin at E15 (Hayashi et al., 1985Hayashi C. Sonoda T. Nakano T. Nakayama H. Kitamura Y. Mast-cell precursors in the skin of mouse embryos and their deficiency in embryos of Sl/Sld genotype.Dev. Biol. 1985; 109: 234-241Crossref PubMed Scopus (22) Google Scholar, Kitamura et al., 1979Kitamura Y. Shimada M. Go S. Presence of mast cell precursors in fetal liver of mice.Dev. Biol. 1979; 70: 510-514Crossref PubMed Scopus (31) Google Scholar, Sonoda et al., 1983Sonoda T. Hayashi C. Kitamura Y. Presence of mast cell precursors in the yolk sac of mice.Dev. Biol. 1983; 97: 89-94Crossref PubMed Scopus (63) Google Scholar). Mature metachromatic mast cells can be found in the eye and skin during embryogenesis (Hayashi et al., 1985Hayashi C. Sonoda T. Nakano T. Nakayama H. Kitamura Y. Mast-cell precursors in the skin of mouse embryos and their deficiency in embryos of Sl/Sld genotype.Dev. Biol. 1985; 109: 234-241Crossref PubMed Scopus (22) Google Scholar, Liu et al., 2015Liu J. Fu T. Song F. Xue Y. Xia C. Liu P. Wang H. Zhong J. Li Q. Chen J. et al.Mast Cells Participate in Corneal Development in Mice.Sci. Rep. 2015; 5: 17569Crossref PubMed Scopus (36) Google Scholar). However, these studies do not clarify the origin of the fetal mast cells or determine whether they contribute to the adult CTMC pool. Herein, we utilized the inducible runt-related transcription factor1 (Runx1-icre) fate-mapping and colony stimulatory factor 1 receptor (Csf1r-icre) fate-mapping systems to study the ontogeny of mast cells. We have shown that early EMPs, late EMPs and fetal HSCs all contributed to fetal mast cells in succession. From late embryogenesis to adult, early EMP-derived mast cells that first colonize tissues are gradually replaced by late EMP-derived mast cells in most connective tissues except in adipose tissue and pleural cavity, leading to late EMP-derived mast cells being a predominant compartment in adult connective tissues, while fetal HSC-derived mast cells are a leading compartment of mucosal mast cells. Unlike MMCs, adult CTMCs in the skin are poorly reconstituted by donor BM (Kitamura et al., 1977Kitamura Y. Shimada M. Hatanaka K. Miyano Y. Development of mast cells from grafted bone marrow cells in irradiated mice.Nature. 1977; 268: 442-443Crossref PubMed Scopus (236) Google Scholar), indicating different underlying mechanisms for the replenishment of these two types of mast cells. To ascertain the BM-dependence of CTMC homeostasis in adulthood more comprehensively, we adoptively transferred adult CD45.1+BM cells into lethally-irradiated CD45.2+ recipient mice and analyzed the mast cell compartment eight months later. We found that CTMCs in the skin, peritoneal cavity, tongue, heart, esophagus, and trachea were poorly repopulated by donor-derived HSCs. In contrast, more than 50% of caecum mast cells representing MMCs were of donor origin at that time (Figure 1A). To exclude the possibility that perinatal circulating hematopoietic precursors might contribute to adult CTMC homeostasis, we performed BM reconstitution assays in newborn mice. Similarly, donor BM-derived hematopoietic precursors also could not reconstitute the CTMCs in the above tissues in the sublethally irradiated CD45.2+ newborn mice after 8 months of transplantation, while half of the circulating leukocytes and MMCs were of donor origin at that time (Figure 1B). These results indicate that CTMCs originate from fetal mast cells that seed the peripheral tissues before birth and are maintained independently of BM-derived HSCs throughout life. As for cecum mast cells, about half were BM-dependent, likely representing intraepithelial MMCs, while another half that were BM-independent may be CTMC-like mast cells in subepithelial connective tissue strata of intestine. To test whether these embryonic-derived mast cells in connective tissues might be radio-resistant and thereby impede reconstitution by BM cells from the donor, we performed reconstitution assays using mast-cell-deficient Kitw-sh/w-sh mice. Indeed, the mast cells in the skin and peritoneal cavity of lethally irradiated Kitw-sh/w-sh mice could be partially reconstituted by donor BM-derived mast cells (Figure 1C). Moreover, donor BM-derived mast cells could also partially reestablish the peritoneal mast cells in recipient mice after deletion of their peritoneal mast cells by water injection (Guermonprez et al., 2013Guermonprez P. Helft J. Claser C. Deroubaix S. Karanje H. Gazumyan A. Darasse-Jèze G. Telerman S.B. Breton G. Schreiber H.A. et al.Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection.Nat. Med. 2013; 19: 730-738Crossref PubMed Scopus (112) Google Scholar, Kanakura et al., 1988Kanakura Y. Kuriu A. Waki N. Nakano T. Asai H. Yonezawa T. Kitamura Y. Changes in numbers and types of mast cell colony-forming cells in the peritoneal cavity of mice after injection of distilled water: evidence that mast cells suppress differentiation of bone marrow-derived precursors.Blood. 1988; 71: 573-580PubMed Google Scholar) (Figure 1D). Thus, BM-derived HSCs are capable of re-establishing these tissue-resident mast cells but only when they are absent. We next went on to verify the presence of mast cells in peripheral tissues at birth. Because Avidin has been confirmed to specifically bind to intracellular granules in mature mast cells (Tharp et al., 1985Tharp M.D. Seelig Jr., L.L. Tigelaar R.E. Bergstresser P.R. Conjugated avidin binds to mast cell granules.J. Histochem. Cytochem. 1985; 33: 27-32Crossref PubMed Scopus (124) Google Scholar), we analyzed the distribution of mast cells in newborn mice by Avidin staining combined with the expression of the stem cell factor receptor c-Kit (CD117), one marker of mast cells. CD117+Avidin+ cells were found in most tissues of newborn mice (Figure 2A). To confirm that these cells were undoubted mast cells, we prepared the cells in skin, peritoneal cavity, spleen, and brain for toluidine blue staining and chloroacetate esterase reaction. As expected, mast cells with metachromatic granules were observed in these tissues (Figure 2B). In the skin, these Avidin+mast cells mainly localized in the dermal layer, while in the spleen, they localized diffusely (Figure 2C). In addition, these Avidin+cells also expressed T1/ST2 (IL33R) (Figure 2D), another marker of mature mast cells. Additionally, CD45+CD11b-CD117+T1/ST2+cells were exclusively Avidin positive, consequently this gating strategy was used to analyze tissue mast cells instead of Avidin staining in subsequent experiments. Together, these results confirm that mast cells seed most tissues and develop into mature mast cells with metachromatic granules before birth. We next investigated the embryonic origin of these tissue-resident mast cells using the Runx1-icre fate-mapping model, whereby a tamoxifen (4’OHT)-inducible Cre recombinase gene with two modified estrogen receptor ligand binding domains at both ends (MercreMer) is expressed under the control of the Runx1 locus (Runx1MercreMer/WT) (Samokhvalov et al., 2007Samokhvalov I.M. Samokhvalova N.I. Nishikawa S. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis.Nature. 2007; 446: 1056-1061Crossref PubMed Scopus (361) Google Scholar). Crossing male Runx1MercreMer/WT mice with female Rosa26loxp-STOP-loxp-EYFP/loxp-STOP-loxp-EYFP mice enable the inducible expression of EYFP tag in Runx1-expressing hematopoieitic cells and their progeny cells from heterozygous Runx1cre/EYFP embryos by a single injection of 4’OHT (Hoeffel and Ginhoux, 2015Hoeffel G. Ginhoux F. Ontogeny of Tissue-Resident Macrophages.Front. Immunol. 2015; 6: 486Crossref PubMed Scopus (198) Google Scholar, Hoeffel et al., 2012Hoeffel G. Wang Y. Greter M. See P. Teo P. Malleret B. Leboeuf M. Low D. Oller G. Almeida F. et al.Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages.J. Exp. Med. 2012; 209: 1167-1181Crossref PubMed Scopus (522) Google Scholar). We injected 4’OHT at E7.5, E8.5, and E9.5 to respectively trace the progeny cells from early EMPs (injected at E7.5), late EMPs (at E8.5), and fetal HSCs (at E9.5) by detecting EYFP+cells (Figure 3A). As mentioned above, mast cells were identified as CD45+CD11b-CD117+T1/ST2+ in newborn mice (Figure 2D). In embryos with 4’OHT-exposure at E7.5, EYFP+ cells accounted for 15%–20% of mast cells in the pleural cavity, adipose tissue, and skin, less than 10% in the rudiments of tongue, heart, lung, and peritoneal cavity, and were sparse in gut and spleen at E18.5; in embryos with 4’OHT-exposure at E8.5, EYFP+ mast cells represented 15%–25% of mast cells at E18.5 in all detected tissues except adipose tissue, where their composition percentage were lower than early EMP-derived mast cells; and in embryos with 4’OHT-exposure at E9.5, EYFP+ mast cells had a leading distribution in the gut (up to 30%), but were less than early EMP-derived mast cells in the skin, adipose tissue, and pleural cavity, and less than late EMP-derived mast cells in the pleural cavity, skin, peritoneal cavity, and lung (Figure 3B). To validate 4’OHT treatments at the precise embryonic age, EYFP+ brain microglia, skin macrophages, and blood neutrophils were simultaneously analyzed in the same mouse. Consistent with previous observations, early EMPs mainly contributed to brain microglia, while late EMPs contributed to more tissue-resident macrophages than fetal HSCs before birth (Figure 3B and Figure S2) (Ginhoux et al., 2010Ginhoux F. Greter M. Leboeuf M. Nandi S. See P. Gokhan S. Mehler M.F. Conway S.J. Ng L.G. Stanley E.R. et al.Fate mapping analysis reveals that adult microglia derive from primitive macrophages.Science. 2010; 330: 841-845Crossref PubMed Scopus (3174) Google Scholar, Hoeffel et al., 2015Hoeffel G. Chen J. Lavin Y. Low D. Almeida F.F. See P. Beaudin A.E. Lum J. Low I. Forsberg E.C. et al.C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages.Immunity. 2015; 42: 665-678Abstract Full Text Full Text PDF PubMed Scopus (665) Google Scholar). To further confirm the contribution of early EMPs to fetal mast cells, the Csf1r-icre fate-mapping system with a Cre reporter controlled by the Csf1r promoter was also exploited to specifically trace Csf1r+EMPs (early EMPs) and their progeny by injection of 4’OHT at E8.5, because early EMPs start to express the Csf1r gene from E8.5 onward (Gomez Perdiguero et al., 2015Gomez Perdiguero E. Klapproth K. Schulz C. Busch K. Azzoni E. Crozet L. Garner H. Trouillet C. de Bruijn M.F. Geissmann F. Rodewald H.R. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors.Nature. 2015; 518: 547-551Crossref PubMed Scopus (1336) Google Scholar, Hoeffel and Ginhoux, 2015Hoeffel G. Ginhoux F. Ontogeny of Tissue-Resident Macrophages.Front. Immunol. 2015; 6: 486Crossref PubMed Scopus (198) Google Scholar, Qian et al., 2011Qian B.Z. Li J. Zhang H. Kitamura T. Zhang J. Campion L.R. Kaiser E.A. Snyder L.A. Pollard J.W. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis.Nature. 2011; 475: 222-225Crossref PubMed Scopus (1853) Google Scholar). We found that injection of 4’OHT at E8.5 mainly labeled the mast cells in the skin, pleural cavity, and adipose tissue. Mast cells in the trachea, tongue, and heart were also labeled but to a lesser extent, and the gut, lung, and spleen were only marginally labeled (Figures 3A and 3C). This result is consistent with our observations in the Runx1cre/EYFP embryos pulsed with 4’OHT at E7.5. Similarly, we detected a large number of EYFP+ microglia, confirming Csf1r+EMPs cells as the main origin of brain microglia. Altogether, these results suggest that fetal tissue-resident mast cells have three hematopoietic origin, but each has different tissue preferences: early EMP-derived mast cells mainly populate the skin, pleural cavity, and adipose tissue; late EMP-derived mast cells distribute in more tissue types and are the predominant population except in adipose tissue and mucosa; and fetal HSC-derived mast cells are a leading population in the mucosa. We next investigated the route of mast cell differentiation from early, late EMPs, and HSCs using the Csf1r-icre and Runx1-icre fate-mapping systems. Integrin β7 is one confirmed marker of MCPs in adult mice (Chen et al., 2005Chen C.C. Grimbaldeston M.A. Tsai M. Weissman I.L. Galli S.J. Identification of mast cell progenitors in adult mice.Proc. Natl. Acad. Sci. USA. 2005; 102: 11408-11413Crossref PubMed Scopus (247) Google Scholar). We therefore attempted to detect the expression of integrin β7 in EYFP+ cells in distinct tissues during embryogenesis. In Csf1rcre/EYFP embryos exposed to 4’OHT at E8.5, integrin β7 only appeared at E11 on both EYFP+ (cells derived from early EMPs) and EYFP- cells in the tissues of the yolk sac, fetal liver, blood, body, and head (Figure 4A). The integrin β7+cells were highly abundant in fetal liver and blood, implying that early EMPs first colonized the fetal liver, and some developed into integrin β7+cells at E11 that were then recruited into developing peripheral tissues (Figure 4B). Furthermore, both EYFP+integrin β7+ and EYFP-integrin β7+ cells in the fetal liver were CD41+CD93-CD117+CD16/32+CD11blow, suggesting that they still possessed the phenotypic properties of early EMPs (Figure 4C). To definitively determine whether these fetal liver integrin β7+cells could give rise to fetal tissue-resident mast cells, we sorted CD45+CD11blowCD117+integrin β7+fetal liver cells from Dsred+/− embryos at E12.5 to E13.5 and adoptively transferred them into embryos at E12.5 to E13.5 in the left uterus of pregnant mice. The embryos in the right uterus were injected with CD45+CD11blowCD117+integrin β7- fetal liver cells as negative controls (Figure 4D). At E18.5, adoptively transferred integrin β7+ fetal liver cells exclusively gave rise to mast cells in the skin and peritoneal cavity, whereas those integrin β7- fetal liver cells displayed granulocyte and monocyte potentials, giving rise mainly to neutrophils, monocytes and macrophages (Figure 4D). Next, we compared the in vitro differential potentials of integrin β7+ and integrin β7- fetal liver cells into mast cells by stem cell factor (SCF) and IL-3 stimulation (Wang et al., 2014Wang D. Zheng M. Qiu Y. Guo C. Ji J. Lei L. Zhang X. Liang J. Lou J. Huang W. et al.Tespa1 negatively regulates FcεRI-mediated signaling and the mast cell-mediated allergic response.J. Exp. Med. 2014; 211: 2635-2649Crossref PubMed Scopus (10) Google Scholar). After 7 days of in vitro culture, colonies were generated from sorted CD45+CD11blowCD117+integrin β7+ fetal liver cells, but not from integrin β7- cells (Figure S3A). In addition to the expression of CD117 and T1/ST2, around 12.9% of mast cells in these colonies expressed FcεRI, a marker of mature mast cells, further demonstrating their mast cell identity. In contrast, cells displaying such phenotypes were largely absent in integrin β7-fetal liver-derived cells (Figure S3B). Thus, CD45+ CD11blowCD117+integrin β7+ cells were fetal MCPs. Similarly, MCPs are also derived from late EMPs or HSCs, but the number of early EMP-derived MCPs was the most at E11.5 (Figure 4E and Figure S3C), indicating that early EMPs were the earliest origin of MCPs. Altogether, integrin β7+ cells from yolk sac EMPs and fetal HSCs are fetal MCPs that first appear at E11. Consequently we analyzed whether integrin β7+ MCPs emerging at E11 colonized and completed their maturation in peripheral tissues by using the Csf1r-icre fate-mapping system. Whole-transcriptome sequencing of early EMPs and their progeny (MCPs, mast cells, and macrophages) during embryogenesis revealed that fetal MCPs acquired the mast cell-specific gene signature from E11.5 and complete their maturation in peripheral tissues (Figure 5A). We found that the mRNAs of mast cell-specific genes, including Mrgprb1, Mcpt4, Ndst2, Zfp9, and Fcer1a, were expressed in EYFP+ integrin β7+ MCPs but not in EYFP+ integrin β7- EMPs in the fetal liver (Dwyer et al., 2016Dwyer D.F. Barrett N.A. Austen K.F. Immunological Genome Project ConsortiumExpression profiling of constitutive mast cells reveals a unique identity within the immune system.Nat. Immunol. 2016; 17: 878-887Crossref PubMed Scopus (219) Google Scholar, McNeil et al., 2015McNeil B.D. Pundir P. Meeker S. Han L. Undem B.J. Kulka M. Dong X. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.Nature. 2015; 519: 237-241Crossref PubMed Scopus (735) Google Scholar). The expression of these genes gradually increased in EYFP+ MCPs in the limbs from E11.5 to E14.5 and in the skin from E16.5 to postnatal day 5 (P5) (Figures 5A and 5B). Similar results were observed in EYFP- cells (Figure S4A). Along with the progressive expression of T1/ST2 from E11.5 to E18.5, the expression of integrin β7 on mast cells was downregulated from E16.5 onward (Figure 5C and Figure S4B). FcεRI was still undetectable on the cell surface of E16.5 mast cells, although we had detected its α subunit at the mRNA level (Figure S4C). We also evaluated the proliferative activity of fetal MCPs using Ki67 staining, and found that MCPs in the skin at E12.5 expressed Ki67 the highest, which was strongly downregulated after birth. Thus, MCPs in tissues had higher proliferative potential before birth that was reduced after birth (Figure 5D). The production of metachromatic granules in mast cells is considered the only gold standard for the maturation of mast cells. Thus we measured the generation of granules in MCPs during embryogenesis using Avidin staining. Not until E16.5 did MCPs begin to produce granules (Figure 5E). To verify that these cells were indeed mature mast cells, we performed classical toluidine blue staining and chloroacetate esterase reaction. Consistent with the Avidin staining, both metachromatic and chloroacetate esterase positive granules were clearly observed in the mast cells of skin and peritoneal cavity at E16.5 but not at E15.5, indicating that E16.5 was the time point when mature mast cells developed in the peripheral tissues. E16.5 skin mast cells had stronger chloroacetate esterase activity when compared with peritoneal mast cells, implying that the heterogeneity across tissues begins as early as this time point (Figure 5F). In summary, integrin β7+ MCPs from the fetal liver seed and complete their maturation in the peripheral tissues at late embryogenesis. We were interested to determine whether the CTMCs from the three hematopoietic waves would differ in their fates after birth until adulthood. Consequently, we traced the EYFP+ mast cells from birth to adulthood using both the Runx1-icre fate-mapping and Csf1r-icre fate-mapping models. In the Csf1r-icre fate-mapping model, early EMP-derived mast cells retained consistently high abundance in adipose tissue and the pleural cavity from birth to adulthood. However, their numbers in skin d" @default.
• W2897650637 created "2018-10-26" @default.
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• W2897650637 title "Adult Connective Tissue-Resident Mast Cells Originate from Late Erythro-Myeloid Progenitors" @default.
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• W2897650637 doi "https://doi.org/10.1016/j.immuni.2018.09.023" @default.
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