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）：一般认为，骨髓中有两种类型的干细胞，即造血干细胞（HSC）和间充质干细胞（MSC），并且它们的分化/重建能力是不同的并且是独立的。彼此。造血干细胞已被证明可以产生血细胞和组织中的一些细胞，例如肥大细胞和破骨细胞。间充质干细胞被认为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) 细胞可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，来自每只受体小鼠的克隆性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。在我们的实验室，通过移植源自单个HSC的克隆细胞，我们已经证明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均源自HSC。我们还记录了成纤维细胞集落形成单位 (CFU-F)，曾被认为是间充质细胞的祖细胞，也源自 HSC。最近，我们成功地从克隆移植了单个造血干细胞的小鼠骨髓细胞和直接来自单个造血祖细胞的小鼠骨髓细胞中产生脂肪细胞。我们还对克隆移植10个月的小鼠骨骼中的骨细胞进行了体内骨细胞的初步观察。总之，这些观察结果表明某些间充质细胞类型并非仅源自 MSC。在本申请中，我们建议研究HSC在正常和病理条件下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会阐明骨髓造血干细胞迄今为止未知的重建潜力，即产生脂肪组织、骨骼和软骨的能力。从这些研究中获得的知识将有助于后续开发治疗肥胖和骨骼和关节疾病的新的、独特的途径。