Role of donorderived fibroblasts in the pathogenic process of lacriimal gland chronic graft-versus-host disease

供体成纤维细胞在泪腺慢性移植物抗宿主病发病过程中的作用

基本信息

批准号：
18591932
负责人：
OGAWA Yoko
金额：
$ 2.57万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Tissue atrophy and excessive fibrosis are prominent histologic features of chronic graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation, but the underlying mechanism remains unknown. We investigated whether the fibroblasts increased at the site of pathogenic fibrosis originated from transplanted donor cells in mouse model of chronic GVHD, focusing on lacrimal gland.In this study, we found the following findings.1) The disease progression of fibrotic area in cGVHD lacrimal gland was demonstrated.2) Heat shock protein 47 (HSP47) was found to be an useful marker of fibroblasts in mouse paraffin embedded tissue sections.3) The chimeric status of accumulated HSP47+ fibroblasts in the lacrimal gland of chronic GVHD mouse model was clearly demonstrated by a series of experiments using lacrimal gland tissue specimens.4) The primary culture was successfully generated from chronic GVHD lacrimal gland of animal models. There were significant differences be … More tween GVHD lacimal gland and control fibroblasts on the ability of cell proloferation and the morphology.5) Cellular source of donor-derived fibroblasts might be mesenchymal stem cells, although it was not confirmed.Since there is no specific treatment proven to be effective for lacrimal gland chronic GVHD at this moment, strategies that inhibit the recruitment of fibroblast precursors into the affected lesion could be a novel therapeutic approach to the fibrotic process in lacrimal gland chronic GVHD.Our study demonstrates, for the first time, the presence of bone marrow-derived fibroblasts in pathogenic fibrosis of cGVHD lacrimal gland. This finding leads us to propose a hypothesis that bone marrow-derived fibroblasts may contribute to the pathogenesis of fibrotic diseases, such as pulmonary fibrosis, liver cirrhosis, scleroderma, and ocular cicatricial pemphigoid. It would be important to further evaluate the chimeric status on multiple chronic GVHD tissues and potential associations between the chimeric status and response to various therapeutic regimens. Less

在同种异体造血干细胞移植后，组织萎缩和过量纤维化是慢性晶粒宿主病（GVHD）的突出组织学特征，但潜在的机制仍然未知。我们研究了在慢性GVHD小鼠模型中起源于移植的供体细胞的致病纤维化部位上的成纤维细胞是否增加，重点是泪腺。在这项研究中，我们发现了以下发现。1）CGVHD链球腺中纤维化面积的进展。 3）慢性GVHD小鼠模型的富含Hsp47+成纤维细胞累积的Hsp47+成纤维细胞的嵌合状态的成纤维细胞清楚地证明了一系列实验，该实验使用了富氏腺体培养物。4）成功地培养了原发性培养物，从慢性GVHD lacr lacr chhd lacr gland lacr chnd lacr gland lacr lacr chd lacr lacr lacr lacr。存在很大的差异……更多的二元GVHD粘膜和对控制能力的成纤维细胞和形态的对照。5）5）供体衍生的成纤维细胞的细胞来源可能是间质干细胞，尽管没有得到特定的治疗。成纤维细胞前体进入受影响的病变可能是泪腺纤维化过程的新型热方法。我们的研究首次证明了CGVHD泪腺致病性纤维化中骨髓衍生的成纤维细胞的存在。这一发现使我们提出了一个假设，即骨髓衍生的成纤维细胞可能有助于纤维化疾病的发病机理，例如肺纤维化，肝肝硬化，硬皮病和眼部尾cicatricial pemphigoid。重要的是要进一步评估多个慢性GVHD组织的嵌合状态以及嵌合状态与对各种治疗方案的反应之间的潜在关联。较少的