Identification of a novel population in the adult bone marrow

描述(申请人提供)：骨髓纤维化是一种病理状态，其特征是成纤维细胞和胶原纤维在骨髓中异常堆积。它可以是特发性的，尽管它最常见的特征是血液系统的各种恶性肿瘤，以及非恶性病理，如甲状旁腺功能亢进症和肾性骨营养不良。近年来，我们通过在成骨细胞中表达一种固有活性的甲状旁腺激素受体(PPR*TG)，建立了一种小鼠骨髓纤维化模型。对这一小鼠模型的分析使我们发现了一种新的骨髓群体，由同时表达间充质和造血细胞标志的细胞组成。这个新的群体，我们也成功地在正常小鼠中发现，似乎在PPR*TG中显著扩大。成纤维细胞是骨髓来源的造血/单核细胞系前体细胞分化为成熟间充质细胞的中间阶段。它们通常见于伤口愈合和病理性纤维化的部位，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，并通过分化为肌成纤维细胞，促进伤口愈合和病理性纤维化。它们还可以在体内和体外分化为脂肪细胞。最近，在进展性骨纤维发育不良患者的皮损中发现了纤维细胞。由于我们最近在骨髓中发现的新细胞，类似于纤维细胞，共表达造血细胞和间充质细胞标志，我们将其命名为纤维细胞样细胞。值得注意的是，关于骨髓中纤维细胞的存在还没有直接的报道。我们目前的工作假设是，像创伤和病理性纤维化一样，骨髓是一个允许从造血祖细胞分化为纤维样细胞的微环境，这些细胞可能对骨髓纤维化和/或骨稳态做出贡献，但机制尚不清楚。为了开始验证我们的假设，我们建议通过研究新发现的骨髓细胞是否可移植和造血源，以及除了I型胶原外是否还表达其他基质蛋白和促纤维化/促血管生成细胞因子来研究它们的特性(目标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)。AIMS 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制的了解，至少在甲状旁腺素受体慢性激活的背景下是这样。

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.