Accessory Cells In Normal and Stress Erythopoiesis

描述(由申请人提供)： 在骨髓发育不良(MDS)和慢性炎症贫血(ACI)中，红细胞生成无效，因为红系祖细胞数量正常，但不适当成熟。在造血器官中，红系祖细胞附着在中央巨噬细胞上，形成红母细胞岛。红系祖细胞和中央巨噬细胞之间的相互作用是红细胞和去核所形成的新生网织红细胞成熟所必需的。炎症细胞因子参与了MDS和ACI的病理生理过程。我假设红系祖细胞和巨噬细胞之间的直接相互作用是红系细胞成熟所必需的，而特定的炎性细胞因子破坏了这些相互作用，导致无效的红细胞生成。我还假设，在网织红细胞进入循环后，网织红细胞与脾巨噬细胞、间质或血管内皮细胞之间的进一步相互作用是网织红细胞完全成熟为红细胞所必需的。在溶血和失血引起的贫血中，红细胞应激导致网织红细胞过早进入循环，并可能由于红系细胞-巨噬细胞相互作用的改变而导致病理性红细胞发育。这项研究将使用小鼠前红细胞分化的体外系统来评估与骨髓或脾巨噬细胞共培养对红细胞增殖、凋亡、细胞表面分子表达和网织红细胞形成的影响。在本系统中，来自红细胞的网织红细胞以及来自去血、贫血小鼠的循环应激网织红细胞将与脾巨噬细胞、脾基质细胞系或内皮细胞系共培养，以评价网织红细胞形成双凹红细胞和细胞表面分子的表达。炎性细胞因子将被添加到共培养中，以测量对红细胞和网织红细胞成熟的抑制作用。比较脾切除小鼠和假手术小鼠循环应激网织红细胞的体内成熟情况。这项拟议的研究将加深我们对MDS和ACI无效红细胞生成的理解，并为其提供潜在的治疗方法。同样，这项研究将有助于了解和治疗溶血性或失血性贫血中循环网织红细胞和辅助细胞之间的相互作用受损。

DESCRIPTION (provided by applicant): Erythropoiesis is ineffective in myelodysplasia (MDS) and the anemia of chronic inflammation (ACI) because erythroid progenitor cells are normal in number, but they do not mature appropriately. In hematopoietic organs, erythroid progenitor cells adhere to a central macrophage forming erythroblastic islands. Interactions between the erythroid progenitor cells and central macrophage are necessary for maturation of both the erythroblasts and the nascent reticulocytes formed by erythroblast enucleation. Inflammatory cytokines are implicated in the pathophysiology of MDS and ACI. I hypothesize that direct interactions between erythroid progenitor cells and macrophages are necessary for erythroid cell maturation and that specific inflammatory cytokines disrupt these interactions, leading to ineffective erythropoiesis. I also hypothesize that after reticulocytes enter the circulation, further interactions between reticulocytes and splenic macrophages, stroma, or vascular endothelium are necessary for complete maturation of the reticulocytes into erythrocytes. In anemias due to hemolysis and blood loss, erythropoietic stress causes premature entry of reticulocytes into the circulation and may lead to pathologic erythrocyte development due to altered erythroid cell-macrophage interactions. The proposed research will use an in vitro system of murine proerythroblast differentiation to evaluate the effects of co-culture with bone marrow or splenic macrophages on erythroblast proliferation, apoptosis, expression of cell surface molecules, and reticulocyte formation. Reticulocytes derived in vitro from erythroblasts in this system as well as circulating stress reticulocytes from phlebotomized, anemic mice will be co-cultured with splenic macrophages, a splenic stromal cell line, or an endothelial cell line to evaluate the reticulocytes for formation of biconcave erythrocytes and expression of cell surface molecules. Inflammatory cytokines will be added to co-cultures to measure inhibitory effects on erythroblast and reticulocyte maturation. ln vivo maturation of circulating stress reticulocytes will be compared in splenectomized and sham-operated mice. The proposed research will enhance our understanding of and provide potential treatment approaches for the ineffective erythropoiesis of MDS and ACI. Similarly, this research will help in understanding and treating the impaired interactions between circulating reticulocytes and accessory cells in hemolytic or blood loss anemias.