Accessory Cells In Normal and Stress Erythopoiesis

描述（由申请人提供）： 红细胞生成在骨髓增生异常（MDS）和慢性炎症性贫血（ACI）中是无效的，因为红系祖细胞数量正常，但它们没有适当成熟。在造血器官中，红系祖细胞粘附于中央巨噬细胞形成成红细胞岛。红系祖细胞和中央巨噬细胞之间的相互作用对于成红细胞和由成红细胞去核形成的新生网织红细胞的成熟是必需的。炎症细胞因子参与MDS和ACI的病理生理学。我推测，红系祖细胞和巨噬细胞之间的直接相互作用是必要的红系细胞成熟和特定的炎症细胞因子破坏这些相互作用，导致无效的红细胞生成。我还假设网织红细胞进入循环后，网织红细胞与脾巨噬细胞、基质或血管内皮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。在由于溶血和失血引起的贫血中，红细胞生成应激导致网织红细胞过早进入循环，并可能由于红细胞-巨噬细胞相互作用的改变而导致病理性红细胞发育。拟议的研究将使用体外系统的小鼠原成红细胞分化，以评估与骨髓或脾巨噬细胞的共培养对成红细胞增殖，细胞凋亡，细胞表面分子的表达和网织红细胞形成的影响。将体外来源于该系统中成红细胞的网织红细胞以及来自放血贫血小鼠的循环应激网织红细胞与脾巨噬细胞、脾基质细胞系或内皮细胞系共培养，以评价网织红细胞的双凹红细胞形成和细胞表面分子表达。将向共培养物中加入炎性细胞因子，以测量对成红细胞和网织红细胞成熟的抑制作用。将在脾切除和假手术小鼠中比较循环应激网织红细胞的体内成熟。本研究将为MDS和ACI患者的红细胞生成障碍提供新的治疗方法。同样，这项研究将有助于理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受损的相互作用。

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.