Role of resident mesenchymal stem cells in lung allograft rejection

描述（由申请人提供）：慢性排斥反应或闭塞性细支气管炎（BO）仍然是肺移植后长期生存的主要障碍。BO是对反复或慢性损伤的移植物重塑反应，但移植物-而不是宿主来源的细胞在BO发病机制中的作用仍有待研究。我们最近在人肺同种异体移植物的支气管肺泡灌洗中鉴定出一群供体来源的或肺驻留的间充质干细胞（LR-MSC）。我们现在发现，灌洗液中这些细胞的数量与同种异体移植物损伤的证据直接相关，并预测肺功能的下降（闭塞性细支气管炎综合征（BOS））。我们的初步数据进一步证明，LR-MSC能够抑制T细胞反应并分化为纤维化肌成纤维细胞。LR-MSC衍生的前列腺素（PGE 2）作为T细胞活化的旁分泌抑制剂和作为其纤维化分化的自分泌抑制剂是重要的。我们假设LR-MSCs参与肺移植反应，其数量和功能可作为预测BO发展的生物标志物。我们进一步提出，前列腺素合成和反应缺陷的获得，促纤维化环境促进的现象，触发了LR-MSC表型从免疫调节到促纤维化的“转换”。本申请的目的是利用我们研究直接来自肺同种异体移植物的LR-MSCs的独特能力来了解调节LR-MSCs纤维化分化的机制。本研究将（1）利用来自正常同种异体肺移植物的LR-MSCs，（一种移植物衍生的细胞，其响应于损伤而积累）和局部细胞因子环境，集中于PGE 2在这种相互作用中的作用;（2）采用配对病例对照研究确定LR-从BOS患者分离的MSC表现出改变的表型，其特征在于分泌和响应PGE 2的能力降低，导致纤维化分化倾向增加和;（3）采用前瞻性队列研究，前瞻性地确定在人肺同种异体移植物中，BAL中LR-MSC的数量及其纤维增殖表型是否预测BOS的发生和进展。这项申请代表了首次尝试研究这种新的移植物来源的多能间充质祖细胞的人口，并将提供重要的机制的见解，他们的作用，适应性和适应不良反应肺同种异体移植物损伤。公共卫生相关性：我们提出的研究将是第一个调查肺驻留间充质干细胞作为肺移植慢性排斥反应的生物标志物，并提供新的机制信息，在人类肺移植慢性同种异体排斥反应的细胞和生化调节剂。

DESCRIPTION (provided by applicant): Chronic rejection or bronchiolitis obliterans (BO) continues to be the major impediment to long-term survival after lung transplantation. BO is a graft remodeling response to repeated or chronic injury, but the role of graft- as opposed to host-derived cells in the pathogenesis of BO remains to be investigated. We have recently identified in bronchoalveolar lavage from human lung allografts a population of donor-derived or lung resident mesenchymal stem cells (LR-MSCs). We now show that the number of these cells in lavage fluid correlates directly with evidence of allograft injury and predict decline in lung functions (bronchiolitis obliterans syndrome (BOS)). Our preliminary data further demonstrate that LR-MSCs are capable of both inhibiting T cell responses and undergoing differentiation to fibrogenic myofibroblasts. LR-MSC-derived prostaglandin (PGE2) is important as both a paracrine inhibitor of T cell activation and as an autocrine inhibitor of their fibrogenic differentiation. We hypothesize that LR-MSCs participate in lung allograft responses and that their numbers and functions serve as biomarkers which predict the development of BO. We further propose that acquisition of a defect in prostaglandin synthesis and response, a phenomenon promoted by pro-fibrotic milieu, triggers a "switch" in LR-MSC phenotype from immunoregulatory to pro-fibrotic. The aim of this application is to understand the mechanisms that regulate the fibrotic differentiation of LR-MSCs utilizing our unique ability to study LR-MSCs directly from lung allografts. This application will (1) Utilizing LR-MSCs from normal lung allografts determine the interaction between LR-MSCs (a graft-derived cell which accumulates in response to injury) and local cytokine milieu focusing on the role of PGE2 in this interaction; (2) Using a matched case control study determine whether LR-MSCs isolated from patients with BOS demonstrate an altered phenotype marked by a decreased capacity to secrete and respond to PGE2 leading to an increased propensity towards fibrotic differentiation and; (3) Using a prospective cohort study prospectively determine in human pulmonary allografts whether number of LR-MSCs in BAL and their fibroproliferative phenotypes predict onset and progression of BOS. This application represents the first attempt to study this novel population of graft derived multipotent mesenchymal progenitor cells and will provide important mechanistic insights into their role in adaptive and maladaptive responses to lung allograft injury. PUBLIC HEALTH RELEVANCE: Our proposed studies will be the first to investigate lung resident mesenchymal stem cells as biomarkers of chronic rejection in lung transplantation and provide novel mechanistic information regarding cellular and biochemical modulators of chronic allograft rejection in human lung transplantation.