Identification of a novel population in the adult bone marrow

描述（由申请方提供）：骨髓纤维化是一种病理状态，其特征为骨髓中成纤维细胞样细胞和胶原纤维的异常积聚。它可以是特发性的，尽管它最常见的是造血系统的各种恶性肿瘤的特征，以及非恶性病变如甲状旁腺功能亢进和肾性骨营养不良的特征。近年来，我们通过在成骨细胞中表达甲状旁腺激素（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一种新的骨髓群体，该群体由表达间充质和造血标志物的细胞组成。我们在正常小鼠中也成功鉴定出的这种新的群体似乎在PPR*Tg中显著扩增。纤维细胞是分化为造血/单核细胞谱系的骨髓来源的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性纤维化的部位发现，并且它们具有造血细胞和间充质细胞的混合特征。它们通过分泌基质和促血管生成因子以及通过分化成肌成纤维细胞来促进伤口愈合和病理性纤维化。它们也可以在体内和体外分化为脂肪细胞。最近，在进行性骨化性纤维发育不良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的新细胞与纤维细胞类似，共表达造血和间充质标志物，因此我们将其命名为“纤维细胞样细胞”。值得注意的是，骨髓中纤维细胞的存在尚未以直接的方式报道。我们目前的工作假设是，骨髓，像伤口和病理性纤维化，是一个允许的微环境，从造血前体分化成纤维细胞样细胞，这些细胞可能有助于骨髓纤维化和/或骨稳态，但机制尚不清楚。为了开始测试我们的假设，我们建议研究我们最近发现的新骨髓细胞的身份，通过研究它们是否可移植和造血来源，以及是否表达，除了I型胶原蛋白，其他基质蛋白和促纤维化/促血管生成细胞因子（Aim I）。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将可能扩大我们对骨髓纤维化发病机制的认识，至少在PTH受体慢性活化的背景下。

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.