Role of resident mesenchymal stem cells in lung allograft rejection

常驻间充质干细胞在肺同种异体移植排斥反应中的作用

• 批准号: 8268427
• 负责人: Vibha N Lama
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268427
• 关键词: Acute; Allografting; Biochemical; Biological Markers; Biological Response Modifiers; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cell Count; Cells; Chronic; Cohort Studies; Data; Defect; Development; Dinoprostone; Donor person; Early Diagnosis; Effector Cell; Equilibrium; Event; Exhalation; Exhibits; Fibrosis; Goals; Health; Human; Immune; Inflammatory; Injury; Interleukin-13; Irrigation; Life; Lipids; Liquid substance; Lung; Lung Transplantation; Matched Case-Control Study; Measures; Mediator of activation protein; Mesenchymal; Mesenchymal Stem Cells; Myofibroblast; Outcome; Participant; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Population; Process; Prostaglandin Receptor; Prostaglandins; Pulmonary Function Test/Forced Expiratory Volume 1; Recruitment Activity; Regulation; Respiratory physiology; Role; Sampling; Signal Transduction; Stem cells; Syndrome; Synthetic Prostaglandins; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Time; Transplant Recipients; Transplantation; allograft rejection; autocrine; cytokine; enzyme activity; fibrogenesis; in vivo; inhibitor/antagonist; insight; lung allograft; novel; paracrine; prospective; response; response to injury; selective expression; stem cell fate

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.

描述（由申请人提供）：慢性排斥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，但与宿主来源的细胞相反，移植物细胞在 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液中发现了一群来自供体的或肺驻留的间充质干细胞（LR-MSC）。我们现在表明，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 (PGE2) 作为 T 细胞活化的旁分泌抑制剂和纤维形成分化的自分泌抑制剂都很重要。我们假设 LR-MSC 参与肺同种异体移植反应，并且它们的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中的缺陷（一种由促纤维化环境促进的现象）的获得，会触发 LR-MSC 表型从免疫调节向促纤维化的“转变”。本申请的目的是利用我们直接研究来自肺同种异体移植物的 LR-MSC 的独特能力，了解调节 LR-MSC 纤维化分化的机制。该应用将 (1) 利用来自正常肺同种异体移植物的 LR-MSC 确定 LR-MSC（一种因损伤而积累的移植物衍生细胞）和局部细胞因子环境之间的相互作用，重点关注 PGE2 在这种相互作用中的作用； (2) 使用匹配的病例对照研究确定从 BOS 患者中分离的 LR-MSC 是否表现出表型改变，其标志是分泌和响应 PGE2 的能力下降，导致纤维化分化倾向增加； (3) 使用前瞻性队列研究在人肺同种异体移植物中前瞻性地确定 BAL 中 LR-MSC 的数量及其纤维增殖表型是否可以预测 BOS 的发生和进展。该应用代表了研究这种新的移植源性多能间充质祖细胞群体的首次尝试，并将为它们在肺同种异体移植损伤的适应性和适应不良反应中的作用提供重要的机制见解。公共健康相关性：我们提出的研究将是第一个研究肺驻留间充质干细胞作为肺移植慢性排斥反应生物标志物的研究，并提供有关人肺移植慢性同种异体移植排斥的细胞和生化调节剂的新机制信息。