Mesenchymal Stromal Cells in Bronchoalveolar Lavage as Predictors of Bronchiolitis Obliterans Syndrome

Badri, Linda; Murray, Susan; Liu, Lyrica X.; Walker, Neff; Flint, Andrew; Wadhwa, Anish; Chan, Kevin M.; Toews, Galen B.; Pinsky, David J.; Martínez, Fernando J.; Lama, Vibha N.

doi:10.1164/rccm.201005-0742oc

Cited by 67 publications

(68 citation statements)

References 42 publications

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“…This is also supported by a previous study 15 of cytogenetic analyses in sexmismatched lung transplant recipients, in which 98% of the cells from patients with BOS were donor in origin. Recent work 30 demonstrates that an increase in LRMSCs in BAL fluid precedes the development of BOS, further reiterating a potential role of these local-mesenchymal cells in BOS pathogenesis. Whether expression of myofibroblast markers in BAL-derived MSCs can be used as a biomarker of disease onset or severity remains to be investigated.…”

Section: Discussionmentioning

confidence: 86%

Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

Walker

Badri

Wettlaufer

et al. 2011

The American Journal of Pathology

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101

105

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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 ( Chronic allograft rejection develops in up to 60% of patients who undergo lung transplantation by 5 years and is the leading cause of poor long-term outcomes after lung transplantation.1 As with other solid organ transplants, chronic allograft rejection in the lung manifests as a fibrotic response to repeated immune and nonimmune insults, leading to narrowing and obliteration of the small airways, a lesion termed bronchiolitis obliterans (BO). 2Subepithelial and/or intraluminal infiltration by myofibroblasts, differentiated mesenchymal cells with augmented collagen secretory and contractile functions, 3 is noted in human biopsy specimens that demonstrate BO.4 BO presents clinically as an obstructive ventilatory defect termed BO syndrome (BOS).5 BOS is the major cause of graft failure and long-term mortality, with no effective treatment options. 6,7 Understanding the origin of effector myofibroblasts in fibrotic lesions of BO is critical for therapeutic targeting of mechanisms of cell recruitment/differentiation.One potential source of mesenchymal cells participating in this disorganized repair response is the mesenchymal progenitors residing in the graft. The embryonic lung mesenchyme is derived from splanchnic mesoderm during orSupported by grants (R01DK082481 to P.H.K.; RO1HL094311 to M.P.-G.; RO1HL094622

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Section: Discussionmentioning

confidence: 86%

Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

Walker

Badri

Wettlaufer

et al. 2011

The American Journal of Pathology

Self Cite

101

105

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“…Second, this is the most multifaceted study material of BAL-cultured cells comprising over 10 different lung diseases. Although Badri et al 20 have collected a study population composed of 405 BAL samples obtained from 162 lung transplant recipients, they focused on studying bronchiolitis obliterans syndrome. Moreover, as far as we are aware, no other group would have analyzed diagnostic samples with such small volumes of BAL fluids as used in this study.…”

Section: Discussionmentioning

confidence: 99%

Myofibroblasts in interstitial lung diseases show diverse electron microscopic and invasive features

Karvonen

Lehtonen

Sormunen

et al. 2012

Laboratory Investigation

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The characteristic features of myofibroblasts in various lung disorders are poorly understood. We have evaluated the ultrastructure and invasive capacities of myofibroblasts cultured from small volumes of diagnostic bronchoalveolar lavage (BAL) fluid samples from patients with different types of lung diseases. Cells were cultured from samples of BAL fluid collected from 51 patients that had undergone bronchoscopy and BAL for diagnostic purposes. The cells were visualized by transmission electron microscopy and immunoelectron microscopy to achieve ultrastructural localization of alphasmooth muscle actin (a-SMA) and fibronectin. The levels of a-SMA protein and mRNA and fibronectin mRNA were measured by western blot and quantitative real-time reverse transcriptase polymerase chain reaction. The invasive capacities of the cells were evaluated. The cultured cells were either fibroblasts or myofibroblasts. The structure of the fibronexus, and the amounts of intracellular actin, extracellular fibronectin and cell junctions of myofibroblasts varied in different diseases. In electron and immunoelectron microscopy, cells cultured from interstitial lung diseases (ILDs) expressed more actin filaments and a-SMA than normal lung. The invasive capacity of the cells obtained from patients with idiopathic pulmonary fibrosis was higher than that from patients with other type of ILDs. Cells expressing more actin filaments had a higher invasion capacity. It is concluded that electron and immunoelectron microscopic studies of myofibroblasts can reveal differential features in various diseases. An analysis of myofibroblasts cultured from diagnostic BAL fluid samples may represent a new kind of tool for diagnostics and research into lung diseases.

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“…Finally, she provided evidence that patients at increased risk of developing bronchiolitis obliterans exhibited elevated LR-MSC abundance in their bronchiolar lavage fluid. These data indicate a potential usefulness for measuring LR-MSC abundance as an early biomarker for lung transplant failure (63). (65).…”

Section: American Thoracic Society Documentsmentioning

confidence: 78%

An Official American Thoracic Society Workshop Report: Stem Cells and Cell Therapies in Lung Biology and Diseases

Weiss¹,

Chambers²,

Giangreco³

et al. 2015

Annals ATS

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The University of Vermont College of Medicine and the Vermont Lung Center, in collaboration with the NHLBI, Alpha-1 Foundation, American Thoracic Society, European Respiratory Society, International Society for Cell Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop, "Stem Cells and Cell Therapies in Lung Biology and Lung Diseases," held July 29 to August 1, 2013 at the University of Vermont. The conference objectives were to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy and ex vivo bioengineering approaches for lung diseases. These are all rapidly expanding areas of study that both provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, discuss and debate current controversies, and identify future research directions and opportunities for both basic and translational research in cell-based therapies for lung diseases. This conference was a follow-up to four previous biennial conferences held at the University

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Mesenchymal Stromal Cells in Bronchoalveolar Lavage as Predictors of Bronchiolitis Obliterans Syndrome

Cited by 67 publications

References 42 publications

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

Myofibroblasts in interstitial lung diseases show diverse electron microscopic and invasive features

An Official American Thoracic Society Workshop Report: Stem Cells and Cell Therapies in Lung Biology and Diseases

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