Mice carrying certain mutations in the white spotting (W) locus (ie, c-kit) exhibit reduced c-kit tyrosine kinase-dependent signaling that results in mast cellGenetically mast cell-deficient c-kit mutant mice have become a powerful tool for identifying and quantifying the contributions of mast cells in many biological responses in vivo. Mice carrying spontaneous loss-of-function mutations at both alleles of the dominant white spotting (W) locus (ie, c-kit), exhibit a marked reduction in c-kit tyrosine kinase-dependent signaling, resulting in disrupted normal mast cell development and survival, 1,2 and therefore mast cell function, as well as many other phenotypic abnormalities that are unrelated to the mast cell deficiency.
Little is known about the formation of niches, local micro-environments required for stem cell maintenance. Here we develop an in vivo assay for adult hematopoietic stem cell (HSC) niche formation 1-2. With this assay, we identified a population of progenitor cells with surface markers CD45-Tie2-αV+CD105+Thy1.1- (CD105+Thy1-) that when sorted from 15.5 dpc fetal bones (fb) and transplanted under the adult mouse kidney capsule could recruit host-derived blood vessels, produce donor-derived ectopic bones through a cartilage intermediate, and generate a marrow cavity populated by host-derived long term reconstituting HSC (LT-HSC). In contrast, CD45-Tie2-αV+CD105+Thy1+ (CD105+Thy1+) fb progenitors form bone that does not contain a marrow cavity. Suppressing expression of factors involved in endochondral ossification, such as osterix and VEGF, inhibited niche generation 22-24. CD105+Thy1-progenitor populations derived from regions of the fetal mandible or calvaria that do not undergo endochondral ossification formed only bone without marrow in our assay27. Collectively, our data implicates endochondral ossification, bone formation that proceeds through a cartilage intermediate, as a requirement for adult HSC niche formation.
Snake or honeybee envenomation can cause substantial morbidity and mortality, and it has been proposed that the activation of mast cells by snake or insect venoms can contribute to these effects. We show, in contrast, that mast cells can significantly reduce snake-venom-induced pathology in mice, at least in part by releasing carboxypeptidase A and possibly other proteases, which can degrade venom components. Mast cells also significantly reduced the morbidity and mortality induced by honeybee venom. These findings identify a new biological function for mast cells in enhancing resistance to the morbidity and mortality induced by animal venoms.
It is well known that mast cells are derived from hematopoietic stem cells. However, in adult hematopoiesis, a committed mast cell progenitor has not yet been identified in any species, nor is it clear at what point during adult hematopoiesis commitment to the mast cell lineage occurs. We identified a cell population in adult mouse bone marrow, characterized as Lin ؊ c-Kit ؉ Sca-1 ؊ -Ly6c ؊ FcRI␣ ؊ CD27 ؊ 7 ؉ T1͞ST2 ؉ , that gives rise only to mast cells in culture and that can reconstitute the mast cell compartment when transferred into c-kit mutant mast cell-deficient mice. In addition, our experiments strongly suggest that these adult mast cell progenitors are derived directly from multipotential progenitors instead of, as previously proposed, common myeloid progenitors or granulocyte͞macrophage progenitors.hematopoietic stem cell ͉ multipotential progenitor
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