Identification of a novel population in the adult bone marrow

成人骨髓中新群体的鉴定

• 批准号: 8336893
• 负责人: Ernestina Schipani
• 金额: $ 17.59万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8336893
• 关键词: Adipocytes; Adult; Affect; Anemia; Angiogenic Factor; Applications Grants; Blood Circulation; Bone Marrow; Bone Marrow Cells; Cells; Chronic; Collagen Fiber; Collagen Type I; Development; Drosophila pros protein; Erythropoietin; Experimental Models; Fibrosis; Healed; Hematopoietic; Hematopoietic System; Homeostasis; Hyperparathyroidism; ITGAM gene; In Vitro; Knowledge; Lesion; Link; Malignant Neoplasms; Marrow; Mesenchymal; Mus; Myelofibrosis; Myofibroblast; Names; Non-Malignant; Osteoblasts; Osteoclasts; PTPRC gene; Parathyroid Hormone Receptor; Pathogenesis; Pathology; Patients; Population; Proteins; Renal Osteodystrophy; Reporting; Resistance; Site; Skeletal system; Staging; Surface Antigens; Testing; Tissues; Tumor necrosis factor receptor 11b; Work; Wound Healing; bone; cell type; cytokine; healing; in vivo; monocyte; mouse model; novel; precursor cell; progenitor; progressive myositis ossificans; research study

DESCRIPTION (provided by applicant): Marrow fibrosis is a pathological condition characterized by abnormal accumulation in the bone marrow of fibroblastoid cells and collagen fibers. It can be idiopathic, though it is most often a feature of a variety of malignancies of the hematopoietic system, and of non-malignant pathologies such as hyperparathyroidism and renal osteodystrophy. In recent years, we have generated a mouse model of marrow fibrosis by expressing a constitutively active receptor for Parathyroid Hormone (PTH) in osteoblasts (PPR*Tg). The analysis of this mouse model has led us to the discovery of a novel bone marrow population constituted by cells that express both mesenchymal and hematopoietic markers. This novel population, which we have also successfully identified in normal mice, appears to be significantly expanded in PPR*Tg. Fibrocytes are an intermediate stage of differentiation into mature mesenchymal cells of bone marrow-derived precursors of the hematopoietic/monocyte lineage. They are typically found at sites of wound healing and pathological fibroses, and they have mixed features of hematopoietic and mesenchymal cells. They contribute to wound healing and to pathological fibroses by secreting matrix and pro-angiogenic factors, and by differentiating into myofibroblasts. They can also differentiate into adipocytes in vivo and in vitro. More recently, fibrocytes have been found in lesions of patients affected by Fibrodysplasia Ossificans Progressiva. Since the novel cells we have recently identified in the bone marrow, similarly to fibrocytes, co- express hematopoietic and mesenchymal markers, we named them "fibrocyte-like cells". Of note, to this end presence of fibrocytes in the bone marrow has not been reported in a direct fashion. Our current working hypotheses is that the bone marrow, like wounds and pathological fibroses, is a permissive microenvironment for the differentiation of fibroctye-like cells from hematopoietic precursors, and that these cells may contribute to the marrow fibrosis and/or to bone homeostasis with yet unknown mechanisms. In order to start testing our hypotheses, we propose to investigate the identity of the novel bone marrow cells we have recently discovered, by studying whether they are transplantable and of hematopoietic origin, and whether express, in addition to type I collagen, other matrix proteins and pro-fibrotic/proangiogenic cytokines (Aim I). Moreover, we will test whether these cells differentiate into osteoblasts and/or adipocytes (Aim II). The accomplishment of the experiments described in Aims I and II will likely expand our knowledge on the pathogenesis of bone marrow fibrosis, at least in a context of chronic activation of the PTH receptor.

描述（由申请人提供）：骨髓纤维化是一种病理状况，其特征是成纤维细胞和胶原蛋白纤维的骨髓异常积累。它可能是特发性的，尽管它通常是造血系统多种恶性肿瘤的特征，以及诸如甲状旁腺功能亢进症和肾脏骨病疗法等非恶性病理学的特征。近年来，我们通过表达成骨细胞中甲状旁腺激素（PTH）的组成型活性受体（PPR*TG）来产生骨髓纤维化的小鼠模型。对这种小鼠模型的分析使我们发现了表达间充质和造血标记的细胞组成的新型骨髓种群。我们在正常小鼠中也成功识别的这种新型人群在PPR*TG中似乎显着扩展。纤维细胞是分化为造血/单核细胞谱系的骨髓衍生前体的成熟间充质细胞的中间阶段。它们通常在伤口愈合和病理纤维纤维的部位发现，并且具有造血和间质细胞的混合特征。它们通过分泌基质和促血管生成因子以及区分成肌纤维细胞来导致伤口愈合和病理纤维纤维。它们还可以在体内和体外区分脂肪细胞。最近，在受纤维增生性浮肿症患者的病变中发现了纤维细胞。由于我们最近在骨髓中鉴定出的新细胞，类似于纤维细胞，共同表达造血和间充质标记，因此我们将其命名为“纤维细胞样细胞”。值得注意的是，尚未直接报道骨髓中纤维细胞的最终存在。我们目前的工作假设是，像伤口和病理纤维纤维一样，骨髓是一种允许性的微环境，用于从造血前体中分化类似纤维细胞的细胞，并且这些细胞可能有助于骨髓纤维化和/或对骨稳态具有但不知名的机制。为了开始检验我们的假设，我们建议通过研究它们是否是可移植和造血起源的新型骨髓细胞的身份，以及除了I型胶原蛋白，其他基质蛋白和纤维化/纤维性/促态性细胞（Aim I）之外，是否表达出来。此外，我们将测试这些细胞是否分化为成骨细胞和/或脂肪细胞（AIM II）。目标I和II中描述的实验的完成可能会扩大我们对骨髓纤维化发病机理的了解，至少在PTH受体的长期激活的背景下。