Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts.
Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts.
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DOI：
10.1016/j.ajpath.2011.01.058
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发表时间：
2011-06
期刊：
影响因子：
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通讯作者：
N. Walker;Linda N Badri;S. Wettlaufer;A. Flint;U. Sajjan;P. Krebsbach;V. Keshamouni;M. Peters-Golden;V. Lama
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文献类型：
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作者：
N. Walker;Linda N Badri;S. Wettlaufer;A. Flint;U. Sajjan;P. Krebsbach;V. Keshamouni;M. Peters-Golden;V. Lama
小气道的纤维化闭塞导致进行性气流阻塞，称为闭塞性细支气管炎综合征（BOS），是肺移植后不良结局的主要原因。我们最近证明，供体来源的多能间充质干细胞（MSC）的人口可以从人肺移植受体的支气管肺泡灌洗液（BAL）流体分离。在此，我们研究了这些细胞的器官特异性，并调查了肺移植后局部间充质祖细胞在纤维化中的作用。我们证明，人肺同种异体移植衍生的MSC独特地表达胚胎肺间充质相关的转录因子，与骨髓MSC相比，在肺中观察到的叉头/翼螺旋转录因子叉头盒（FOXF 1）的表达高35，000倍。在存在与BOS相关的促纤维化介质（包括转化生长因子-β和IL-13）的情况下，观察到从正常肺同种异体移植物中分离的MSC的纤维化分化。与非BOS对照组相比，从BOS患者中分离的MSC表现出α-SMA和胶原I的表达增加，与稳定的体内纤维化表型一致。FOXF 1 mRNA在BAL细胞团中的表达与BAL液中MSC的数量相关，原位杂交显示纤维化病变中的肌成纤维细胞表达FOXF 1。这些数据表明，在成人肺纤维化过程中，局部组织特异性、器官驻留性、间充质前体细胞发挥关键作用。
Fibrotic obliteration of the small airways leading to progressive airflow obstruction, termed bronchiolitis obliterans syndrome (BOS), is the major cause of poor outcomes after lung transplantation. We recently demonstrated that a donor-derived population of multipotent mesenchymal stem cells (MSCs) can be isolated from the bronchoalveolar lavage (BAL) fluid of human lung transplant recipients. Herein, we study the organ specificity of these cells and investigate the role of local mesenchymal progenitors in fibrogenesis after lung transplantation. We demonstrate that human lung allograft–derived MSCs uniquely express embryonic lung mesenchyme–associated transcription factors with a 35,000-fold higher expression of forkhead/winged helix transcription factor forkhead box (FOXF1) noted in lung compared with bone marrow MSCs. Fibrotic differentiation of MSCs isolated from normal lung allografts was noted in the presence of profibrotic mediators associated with BOS, including transforming growth factor-β and IL-13. MSCs isolated from patients with BOS demonstrated increased expression of α-SMA and collagen I when compared with non-BOS controls, consistent with a stablein vivofibrotic phenotype. FOXF1 mRNA expression in the BAL cell pellet correlated with the number of MSCs in the BAL fluid, and myofibroblasts present in the fibrotic lesions expressed FOXF1 byin situhybridization. These data suggest a key role for local tissue-specific, organ-resident, mesenchymal precursors in the fibrogenic processes in human adult lungs.