CD34 expression by mast cells: of mice and men

Abstract

calcium by sodium citrate used as an anticoagulant with blood collection. However, protein-S dimerization occurs at concentrations far above the plasma concentration: "at 17 M, the associated product is principally a dimer." 2 Inspection of Figure 5 of the paper by Pauls et al 2 indicates that, at the free protein-S concentration present in plasma (ϳ 150 nM), protein S is principally a monomer.In spite of this, Dr Mann believes that inhibitory protein-S dimers are present at the start of our experiments, and that slow depolymerization of these dimers after recalcification of plasma invalidated our conclusions. 1 We refuted this possibility by recalcifying the plasma 15 minutes before initiation of thrombin generation with tissue factor/phospholipid. This provided ample time for the Ca 2ϩ -induced conformational changes of vitamin-K-dependent proteins to occur, and for depolymerization of protein-S dimers if present. Figure 1 shows that after "pre"-recalcification of plasma the activated protein C (APC)-independent inhibitory effect of protein S on thrombin generation prevailed.The endogenous thrombin potentials (ETPs) determined in the absence of functional protein S were similar without and with preincubation of plasma with CaCl 2 (Figure 1). In the presence of protein S (Figure 1 open symbols), the ETP determined in plasma preincubated with CaCl 2 (521 nM thrombin min) was even lower than the ETP of plasma that was not preincubated with CaCl 2 (659 nM thrombin min). Protein S decreased the ETP in freshly recalcified citrated plasma by 30%, compared with 40% when plasma was preincubated with CaCl 2 , and thus became an even better inhibitor of thrombin generation. Moreover, if protein-S dimers in citrated plasma had caused the observed phenomena, the inhibitory effect of protein S on thrombin generation would have been abrogated at high phospholipid concentrations. 2 However, increasing phospholipid concentrations did not affect the anticoagulant potential of protein S in plasma. 1 This demonstrates that the inhibition of thrombin formation by protein S in plasma is not due to competition for phospholipid binding sites.Dr Mann raised an important point regarding the effect of the thrombin substrate on thrombin generation. Indeed, it has been shown that the measured ETP increases with increasing substrate concentrations, 5 likely due to the fact that the substrate protects thrombin against inhibition by antithrombins. However, it should be emphasized that only free thrombin (ie, thrombin that is not occupied by substrate) will be available for feedback reactions. Surprisingly, when the free-thrombin concentrations present in plasma were calculated using the Michaelis-Menten constant (K m ) and substrate concentrations, superimposable thrombin generation curves (free thrombin versus time) were obtained. 5 This indicates that the generation of thrombin hardly depends on the action of thrombin but that another component is rate limiting, namely factor Xa, 6 and that the presence of the substrate has virtually no ...

Mast cells are an essential hematopoietic component for polyp development

“…MC requirement was confirmed by using mice reconstituted with c-kit-defective BM (KitW-sh/KitW-sh) (40,41). Although human CD34 antigen expression ceases as MCp differentiate into mature MC in the peripheral tissues, migrating MCp express the antigen and, thus, should still be valid targets for therapy (7). Additionally, because deletion of the CD34-encoding gene has no obvious effects on murine development or steady-state immune responses, strategies to target this antigen in human MC are likely to be well tolerated.…”

“…This notion is further strengthened by reports that, in human, iMC lack CD34 (6), because we previously have shown that, although the human Cd34 gene is expressed in trafficking MCp, it is shut off as they differentiate into mature MC in the periphery (reviewed in ref. 7). Our revelation that the iMC are MC should greatly enhance the development of additional interventional therapies.…”

“…They elaborate a potent array of cytokines, proteases, and inflammatory mediators (including TNF␣, IL-6, TGF-␤, VEGF, MMP2, and MMP9), which are known to be involved in tissue remodeling and angiogenesis. These cells are responsive to CCL9, and we have recently shown that they require the sialomucin CD34 (and CD43) for efficient trafficking in vivo (7,8). Although mastocytosis is frequently associated with the emergence of tumors (6)(7)(8)(9)(10)(11)(12)(13), their role in tumor progression or rejection is only beginning to be studied.…”

Lin− CD34hi CD117int/hi FcεRI+ cells in human blood constitute a rare population of mast cell progenitors

“…CD34 is lost during mast cell maturation. 41 Therefore, the mast cell progenitors identified in the present study are likely more immature than CD34 2 CD117 1 blood cells with mast cell-forming capacity quantified in mastocytosis patients. 42 To summarize, we have identified a rare population of human mast cell progenitors in blood, which gives rise to predominantly mast cells, although the limited cell division capacity and partial loss of FceRI after culture in vitro prevent us from concluding their full commitment to the mast cell lineage.…”

CD34 facilitates the development of allergic asthma

“…17 CD34 is a cell-surface sialomucin originally identified as a marker of hematopoietic stem cells (HSCs), early hematopoietic progenitors, and vascular endothelia 18 and was more recently identified on mast cells and eosinophils. 19,20 In fact, it was shown that in a mouse model of asthma, 50% of the recruited eosinophils were CD34 ϩ . 20 Surprisingly, despite the wide attention CD34 has garnered as a marker of hematopoietic precursors (Ͼ 14 000 citations), little is know of its function on these cells.…”