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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094622-04
Application #
8268427
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Belloli, Elizabeth A; Lama, Vibha N (2016) Spirometry States the Obvious: Recognizing Bronchiolitis Obliterans Syndrome Early after Hematopoietic Cell Transplantation. Ann Am Thorac Soc 13:1883-1884
Walker, Natalie M; Belloli, Elizabeth A; Stuckey, Linda et al. (2016) Mechanistic Target of Rapamycin Complex 1 (mTORC1) and mTORC2 as Key Signaling Intermediates in Mesenchymal Cell Activation. J Biol Chem 291:6262-71
Shah, R J; Diamond, J M; Cantu, E et al. (2015) Objective Estimates Improve Risk Stratification for Primary Graft Dysfunction after Lung Transplantation. Am J Transplant 15:2188-96
Dickson, Robert P; Erb-Downward, John R; Prescott, Hallie C et al. (2015) Intraalveolar Catecholamines and the Human Lung Microbiome. Am J Respir Crit Care Med 192:257-9
Mimura, Takeshi; Walker, Natalie; Aoki, Yoshiro et al. (2015) Local origin of mesenchymal cells in a murine orthotopic lung transplantation model of bronchiolitis obliterans. Am J Pathol 185:1564-74
Belloli, Elizabeth A; Wang, Xin; Murray, Susan et al. (2015) Longitudinal Forced Vital Capacity Monitoring as a Prognostic Adjunct after Lung Transplantation. Am J Respir Crit Care Med 192:209-18
Dickson, Robert P; Erb-Downward, John R; Prescott, Hallie C et al. (2014) Analysis of culture-dependent versus culture-independent techniques for identification of bacteria in clinically obtained bronchoalveolar lavage fluid. J Clin Microbiol 52:3605-13
Dickson, Robert P; Erb-Downward, John R; Freeman, Christine M et al. (2014) Changes in the lung microbiome following lung transplantation include the emergence of two distinct Pseudomonas species with distinct clinical associations. PLoS One 9:e97214
Walker, Natalie M; Badri, Linda N; Wadhwa, Anish et al. (2012) Prostaglandin E2 as an inhibitory modulator of fibrogenesis in human lung allografts. Am J Respir Crit Care Med 185:77-84
Badri, Linda; Lama, Vibha N (2012) Lysophosphatidic acid induces migration of human lung-resident mesenchymal stem cells through the β-catenin pathway. Stem Cells 30:2010-9

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