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

组织萎缩和过度纤维化是同种异体造血干细胞移植后慢性移植物抗宿主病（GVHD）的显著组织学特征，但其潜在机制尚不清楚。我们研究了慢性GVHD小鼠模型中，以泪腺为重点，在移植供体细胞引起的致病性纤维化部位，成纤维细胞是否增加。在这项研究中，我们发现了以下发现。1)证实cGVHD泪腺纤维化区病变进展。2)在小鼠石蜡包埋组织切片中发现热休克蛋白47 （HSP47）是成纤维细胞的有用标记物。3)通过泪腺组织标本的一系列实验，明确了HSP47+成纤维细胞在慢性GVHD小鼠模型泪腺中的嵌合状态。4)成功获得慢性GVHD动物模型泪腺原代培养物。GVHD乳腺与对照成纤维细胞在细胞增殖能力和形态上存在显著差异。5)供体源性成纤维细胞的细胞来源可能是间充质干细胞，但尚未得到证实。由于目前还没有特异性的治疗方法被证明对泪腺慢性GVHD有效，因此抑制成纤维细胞前体向病变募集的策略可能是治疗泪腺慢性GVHD纤维化过程的一种新的治疗方法。我们的研究首次证实了骨髓源性成纤维细胞在cGVHD泪腺致病性纤维化中的存在。这一发现使我们提出一种假设，即骨髓来源的成纤维细胞可能参与纤维化疾病的发病机制，如肺纤维化、肝硬化、硬皮病和眼瘢痕性类天疱疮。进一步评估多种慢性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具有重要意义。少

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