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Hematopoietic Origin of Mesenchymal Cells

间充质细胞的造血起源

基本信息

批准号：
7575079
负责人：
Makio Ogawa
金额：
$ 26.78万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2011-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): It is generally believed that there are two types of stem cells in the bone marrow, i.e. hematopoietic stem cells (HSCs) and mesenchymal (MSCs) and that their repertoire of differentiation/reconstituting potentials are distinct and separate from each other. HSCs have been shown to produce blood cells and some cells in the tissues such as mast cells and osteoclasts. MSCs are thought to be responsible for a number of mesenchymal cells including fibroblasts, adipocytes, chondrocytes and osteocytes. Recently, studies have begun to question the distinction between the potentials of HSCs and MSCs. For example, transplantation of 3000 side population (SP) cells that are highly enriched for HSCs generated osteoblasts in vivo. Also in a transplantation study using retrovirally transduced bone marrow cells, a close relationship was suggested by a common retroviral integration site in clonogenic hematopoietic cells and osteoprogenitors from each of the recipient mice. In our laboratory, by transplanting clonal cells derived from single HSCs, we have documented that a number of tissue fibroblasts/myofibroblasts such as glomerular mesangial cells, brain microglial cells, fibroblasts in cardiac valve and tumor-associated fibroblasts are derived from HSCs. We have also documented that fibroblast colony-forming units (CFU-F), which had been thought to be progenitors for mesenchymal cells, are also derived from HSCs. Most recently, we succeeded in generating adipocytes in vitro from the bone marrow cells of mice that had been clonally engrafted with single HSCs and directly from single hematopoietic progenitors. We also made a preliminary observation of osteocytes in vivo in the bones of mice that had been clonally engrafted for 10 months. Together, these observations suggest that some mesenchymal cell types are not derived solely from the MSC. In this application, we propose to investigate the potential of the HSC to give rise to fibroblasts, adipocytes, osteocytes and chondrocytes in vitro and in vivo under both normal and pathological conditions. Project Narrative: Studies described in this application are likely to elucidate hitherto unknown reconstitution potentials of bone marrow hematopoietic stem cells, i.e. abilities to generate fat tissues, bones and cartilages. The knowledge gained from these studies will allow subsequent development of new, unique avenues of therapy for obesity and diseases of bones and joints.

描述（由申请人提供）：通常认为骨髓中有两种类型的干细胞，即造血干细胞（HSC）和间充质细胞（MSC），并且它们的分化/重建潜能库是不同的并且彼此分离。已显示HSC产生血细胞和组织中的一些细胞，如肥大细胞和破骨细胞。MSC被认为是负责许多间充质细胞，包括成纤维细胞，脂肪细胞，软骨细胞和骨细胞。最近，研究已经开始质疑HSC和MSC的潜力之间的区别。例如，移植高度富集HSC的3000个侧群（SP）细胞在体内产生成骨细胞。同样在使用逆转录病毒转导的骨髓细胞的移植研究中，通过来自每个受体小鼠的克隆生成造血细胞和骨祖细胞中的共同逆转录病毒整合位点表明了密切的关系。在本实验室，通过移植单个HSC的克隆细胞，我们已经证明了许多组织成纤维细胞/肌成纤维细胞，如肾小球系膜细胞，脑小胶质细胞，心脏瓣膜成纤维细胞和肿瘤相关成纤维细胞来源于HSC。我们还证明了成纤维细胞集落形成单位（CFU-F），这一直被认为是间充质细胞的祖细胞，也来自造血干细胞。最近，我们成功地在体外产生脂肪细胞从小鼠的骨髓细胞克隆移植与单一的造血干细胞和直接从单一的造血祖细胞。我们还对克隆移植10个月的小鼠骨中的骨细胞进行了体内初步观察。总之，这些观察结果表明，一些间充质细胞类型不仅仅来源于MSC。在本申请中，我们建议在正常和病理条件下研究HSC在体外和体内产生成纤维细胞、脂肪细胞、骨细胞和软骨细胞的潜力。项目叙述：本申请中描述的研究可能阐明骨髓造血干细胞迄今未知的重建潜力，即产生脂肪组织、骨和软骨的能力。从这些研究中获得的知识将允许随后开发新的，独特的治疗肥胖和骨骼和关节疾病的途径。