OSTEOBLASTS AND HEMATOPOIETIC MICROENVIRONMENT

造血干细胞分化发生在直接靠近 成骨细胞存在于骨髓腔中。我们假设这是 在生命早期建立亲密的身体联系是为了促进 骨和造血细胞之间的相互作用。为了测试这一点 假设我们将确定人类成骨细胞是否是 基本的造血生长因子。我们的调查将利用 共培养和分子生物学方法的结合 确定成骨细胞来源的细胞因子是否会影响 造血干细胞的存活、增殖和成熟。 为了达到这些目标，我们开发了一种原代人类成骨细胞。 纯化和培养系统，使我们能够在 与世隔绝。我们的初步结果表明，这些细胞支持 原始CD34+细胞的存活和增殖，而显然 将它们保持在原始状态。我们希望能确定是什么活动 是造成这一新奇效果的原因。 这些调查的直接临床相关性包括：i) 细胞因子合成改变对骨髓损伤的反应，如 骨髓炎和/或周围组织的感染，如牙周组织 疾病？二)如果成骨细胞有助于维持正常 造血，我们能降低相关的发病率和死亡率吗 通过改变成骨细胞功能进行骨髓移植？Iii) 最后，有一天，这些研究可能会促进基因治疗 通过描述造血功能异常所需的因素 转导的造血干细胞的存活。

Hematopoietic stem cell differentiation occurs in direct proximity to osteoblasts with in the bone marrow cavity. We hypothesize that this intimate physical association established early in life is to facilitate interactions between bone and hematopoietic cells. To test this hypothesis we will determine whether human osteoblasts are a source of essential hematopoietic growth factors. Our investigations will utilize a combination of co-culture and molecular biological approaches to determine whether cytokines derived from osteoblasts influence hematopoietic stem cell survival, proliferation and maturation. Toward these aims we have developed an primary human osteoblast purification and culture system which allows us to study these cells in isolation. Our preliminary results indicate that these cells support the survival and proliferation of primitive CD34+ cells, while apparently maintaining them in a primitive state. We hope to pin down what activity is responsible for this novel effect. The direct clinical relevance of these investigations includes: i) Is cytokine synthesis altered in response to marrow injury as in osteomyelitis and/or infections in surrounding tissues as in periodontal diseases? ii) If osteoblasts contribute to the maintenance of normal hematopoiesis, can we decrease the morbidity and mortality associated with bone marrow transplantation by altering osteoblast function? iii) And finally, one day these investigations may facilitate gene therapy for hematopoietic abnormalities by delineating the factors necessary for the survival of transduced hematopoietic stem cells.