Bone marrow-derived progenitor cells in end-stage lung disease patients

BMC Pulmonary Medicine

Thomas K Waddell¹  Shaf Keshavjee¹  Lianne G Singer¹  Masaaki Sato¹  Marcelo Cypel¹  Geoffrey T de Couto²  Kalvin Lung¹  Sarah E Gilpin¹ 

[1] Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, North Wing, 9N - 949, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada;Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, University of Toronto, Toronto, Ontario, Canada

关键词: Migration;    Lung progenitor;    Clara cell;    Fibrocytes;   

Others  :  1109748
DOI  :  10.1186/1471-2466-13-48

 received in 2013-01-15, accepted in 2013-07-25,  发布年份 2013

【 摘 要 】

Background

Chronic lung diseases are marked by progressive inflammation, tissue damage and remodelling. Bone marrow-derived progenitor cells may contribute to these processes. The objectives of this study were to (1) to quantify CD45⁺Collagen-1⁺ fibrocytes and a novel epithelial-like population of bone marrow-derived cells, which express Clara Cell Secretory Protein, in patients at the time of lung transplant and (2) to evaluate mediators that may act to recruit these cells during injury.

Methods

Using an observational design, progenitor cells were quantified by flow cytometry from both bone marrow (BM) and peripheral blood (PB). Migration was tested using in vitro transwell assays. Multiplex bead-based assays were used to quantify plasma cytokines.

Results

An increase in CD45⁺Collagen-1⁺ fibrocytes was found in pulmonary fibrosis and bronchiolitis obliterans patients. Cystic fibrosis patients had an increase in CCSP⁺ cells in both the BM and PB. The proportion of CCSP⁺ cells in the BM and PB was correlated. CCSP⁺ cells express the chemokine receptors CCR2, CCR4, CXCR3, and CXCR4, and significantly migrated in vitro toward Stromal Derived Factor-1 (SDF-1) and Stem Cell Growth Factor-β (SCGF-β). Plasma cytokine levels differed between disease groups, with a significant correlation between SCGF-β and CCSP⁺ cells and between Monocyte Chemotactic Protein-1 and fibrocytes.

Conclusions

Different bone marrow-derived cells are found in various lung diseases. Increased fibrocytes were associated with fibrotic lung diseases. An increase in the novel CCSP⁺ epithelial-like progenitors in cystic fibrosis patients was found. These differences may be mediated by alterations in plasma cytokines responsible for cell recruitment.

【 授权许可】

   
2013 Gilpin et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]de Perrot M, Chaparro C, McRae K, Waddell TK, Hadjiliadis D, Singer LG, Pierre AF, Hutcheon M, Keshavjee S: Twenty-year experience of lung transplantation at a single center: influence of recipient diagnosis on long-term survival. J Thorac Cardiovasc Surg 2004, 127(5):1493-1501.
• [2]Fraire AT: Inflammation. In Molecular pathology of lung diseases. Edited by Zander DSP, Jagirdar H, Haque J, Barrios AR. New York, NY: Springer; 2008:459-470.
• [3]Brody SL, Atkinson JJ, Brody SL, Atkinson JJ: Epithelial repair and regeneration. In Molecular pathology of lung diseases. Edited by Zander DSP, Jagirdar H, Haque J, Barrios AR. New York, NY: Springer; 2008:476-490.
• [4]Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, Brigham KL: Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 2005, 33(2):145-152.
• [5]Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG: Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 2003, 100(14):8407-8411.
• [6]Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, Liles WC, Stewart DJ: Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 2010, 182(8):1047-1057.
• [7]Wagers AJ, Sherwood RI, Christensen JL, Weissman IL: Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002, 297(5590):2256-2259.
• [8]Wong AP, Keating A, Lu WY, Duchesneau P, Wang X, Sacher A, Hu J, Waddell TK: Identification of a bone marrow-derived epithelial-like population capable of repopulating injured mouse airway epithelium. J Clin Invest 2009, 119(2):336-348.
• [9]Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM: Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004, 114(3):438-446.
• [10]Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J, Margetts PJ, Farkas L, Dobranowski J, Boylan C, et al.: Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009, 179(7):588-594.
• [11]Gilpin SE, Lung KC, Sato M, Singer LG, Keshavjee S, Waddell TK: Altered progenitor cell and cytokine profiles in bronchiolitis obliterans syndrome. J Heart Lung Transplant 2012, 31(2):222-228.
• [12]Leigh MW, Kylander JE, Yankaskas JR, Boucher RC: Cell proliferation in bronchial epithelium and submucosal glands of cystic fibrosis patients. Am J Respir Cell Mol Biol 1995, 12(6):605-612.
• [13]Hajj R, Lesimple P, Nawrocki-Raby B, Birembaut P, Puchelle E, Coraux C: Human airway surface epithelial regeneration is delayed and abnormal in cystic fibrosis. J Pathol 2007, 211(3):340-350.
• [14]Lapar DJ, Burdick MD, Emaminia A, Harris DA, Strieter BA, Liu L, Robbins M, Kron IL, Strieter RM, Lau CL: Circulating fibrocytes correlate with bronchiolitis obliterans syndrome development after lung transplantation: a novel clinical biomarker. Ann Thorac Surg 2011, 92(2):470-477.
• [15]Ito C, Sato H, Ando K, Watanabe S, Yoshiba F, Kishi K, Furuya A, Shitara K, Sugimoto S, Kohno H, et al.: Serum stem cell growth factor for monitoring hematopoietic recovery following stem cell transplantation. Bone Marrow Transplant 2003, 32(4):391-398.
• [16]Moore BB, Kolodsick JE, Thannickal VJ, Cooke K, Moore TA, Hogaboam C, Wilke CA, Toews GB: CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. Am J Pathol 2005, 166(3):675-684.
• [17]Gomperts BN, Strieter RM: Fibrocytes in lung disease. J Leukoc Biol 2007, 82:449-456.
• [18]Abe R, Donnelly SC, Peng T, Bucala R, Metz CN: Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 2001, 166(12):7556-7562.
• [19]Petty JM, Sueblinvong V, Lenox CC, Jones CC, Cosgrove GP, Cool CD, Rai PR, Brown KK, Weiss DJ, Poynter ME, et al.: Pulmonary stromal-derived factor-1 expression and effect on neutrophil recruitment during acute lung injury. J Immunol 2007, 178(12):8148-8157.
• [20]Hiraoka A, Sugimura A, Seki T, Nagasawa T, Ohta N, Shimonishi M, Hagiya M, Shimizu S: Cloning, expression, and characterization of a cDNA encoding a novel human growth factor for primitive hematopoietic progenitor cells. Proc Natl Acad Sci USA 1997, 94(14):7577-7582.
• [21]Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, et al.: MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 2007, 13(5):587-596.
• [22]Schwartz V, Lue H, Kraemer S, Korbiel J, Krohn R, Ohl K, Bucala R, Weber C, Bernhagen J: A functional heteromeric MIF receptor formed by CD74 and CXCR4. FEBS Lett 2009, 583(17):2749-2757.
• [23]Arndt U, Wennemuth G, Barth P, Nain M, Al-Abed Y, Meinhardt A, Gemsa D, Bacher M: Release of macrophage migration inhibitory factor and CXCL8/interleukin-8 from lung epithelial cells rendered necrotic by influenza A virus infection. J Virol 2002, 76(18):9298-9306.
• [24]Donnelly SC, Haslett C, Reid PT, Grant IS, Wallace WA, Metz CN, Bruce LJ, Bucala R: Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat Med 1997, 3(3):320-323.