Regulation of transplanted mesenchymal stem cells by the lung progenitor niche in rats with chronic obstructive pulmonary disease

Respiratory Research

Hui-Lan Zhang¹  Jian-Ping Zhao¹  Zhen-Xiang Zhang¹  Yong-Jian Xu¹  Li Mei¹  Bo Zhang¹  Si-Si Wu¹  Xue-Mei Shi¹  Li He²  Wan-Guang Zhang³ 

[1] Department of Respiratory Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095, Jie Fang Road, Han Kou District, Wuhan, Hubei 430030, China;Department of Respiratory Medicine, Jingzhou Central Hospital, Jingzhou, Hubei, China;Department of Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

关键词: Niche;    Alveolar epithelial type II cells;    Mesenchymal stem cells;    Chronic obstructive pulmonary disease;   

Others  :  790364
DOI  :  10.1186/1465-9921-15-33

 received in 2013-11-04, accepted in 2014-03-20,  发布年份 2014

【 摘 要 】

Background

Stem cell transplantation is a promising method for the treatment of chronic obstructive pulmonary disease (COPD), and mesenchymal stem cells (MSCs) have clinical potential for lung repair/regeneration. However, the rates of engraftment and differentiation are generally low following MSC therapy for lung injury. In previous studies, we constructed a pulmonary surfactant-associated protein A (SPA) suicide gene system, rAAV-SPA-TK, which induced apoptosis in alveolar epithelial type II (AT II) cells and vacated the AT II cell niche. We hypothesized that this system would increase the rates of MSC engraftment and repair in COPD rats.

Methods

The MSC engraftment rate and morphometric changes in lung tissue in vivo were investigated by in situ hybridization, hematoxylin and eosin staining, Masson’s trichrome staining, immunohistochemistry, and real-time PCR. The expression of hypoxia inducible factor (HIF-1α) and stromal cell-derived factor-1 (SDF-1), and relationship between HIF-1α and SDF-1 in a hypoxic cell model were analyzed by real-time PCR, western blotting, and enzyme-linked immunosorbent assay.

Results

rAAV-SPA-TK transfection increased the recruitment of MSCs but induced pulmonary fibrosis in COPD rats. HIF-1α and SDF-1 expression were enhanced after rAAV-SPA-TK transfection. Hypoxia increased the expression of HIF-1α and SDF-1 in the hypoxic cell model, and SDF-1 expression was augmented by HIF-1α under hypoxic conditions.

Conclusions

Vacant AT II cell niches increase the homing and recruitment of MSCs to the lung in COPD rats. MSCs play an important role in lung repair and promote collagen fiber deposition after induction of secondary damage in AT II cells by rAAV-SPA-TK, which involves HIF-1α and SDF-1 signaling.

【 授权许可】

   
2014 Zhang et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare PD: The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004, 350:2645-2653.
• [2]Chistiakov DA: Endogenous and exogenous stem cells: a role in lung repair and use in airway tissue engineering and transplantation. J Biomed Sci 2010, 17:92. BioMed Central Full Text
• [3]MacPherson H, Keir PA, Edwards CJ, Webb S, Dorin JR: Following damage, the majority of bone marrow-derived airway cells express an epithelial marker. Respir Res 2006, 7:145.
• [4]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 U S A 2003, 100:8407-8411.
• [5]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, 33:145-152.
• [6]D’Agostino B, Sullo N, Siniscalco D, De Angelis A, Rossi F: Mesenchymal stem cell therapy for the treatment of chronic obstructive pulmonary disease. Expert Opin Biol Ther 2010, 10:681-687.
• [7]Shi XM, Zhang HL, Xiong SD, Zhen GH, Xiong WN, Zhang ZX, Xu YJ, Hu QJ, Zhao JP, Ni W: Cloning of SPA gene promoter and analysis of its transcriptional targeting activity [in chinese]. Chin J Pathophysio 2008, 24:2002-2007.
• [8]Hu QJ, Xiong SD, Zhang HL, Shi XM, Xu YJ, Zhang ZX, Zhen GH, Zhao JP: Altered surfactant protein A gene expression and protein homeostasis in rats with emphysematous changes. Chin Med J (Engl) 2008, 121:1177-1182.
• [9]Zhen G, Xue Z, Zhao J, Gu N, Tang Z, Xu Y, Zhang Z: Mesenchymal stem cell transplantation increases expression of vascular endothelial growth factor in papain-induced emphysematous lungs and inhibits apoptosis of lung cells. Cytotherapy 2010, 12(5):605-614.
• [10]Liu HM, Zhen GH, Zhang ZX, Zhang HL, Gao Y, Wang T, Gu NB, Xu YJ: Effects of bone marrow mesenchymal stem cells transplantation on the apoptosis of alveolar wall cells in papain and Co60 – induced pulmonary emphysema rats. [in chinese]. Chin J Pathophysio 2008, 24:1529-1533.
• [11]Yabana T, Arimura Y, Tanaka H, Goto A, Hosokawa M, Nagaishi K, Yamashita K, Yamamoto H, Adachi Y, Sasaki Y, Isobe M, Fujimiya M, Imai K, Shinomura Y: Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity. J Pathol 2009, 218:350-359.
• [12]Vernooy JH, Dentener MA, van Suylen RJ, Buurman WA, Wouters EF: Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology. Am J Respir Cell Mol Biol 2002, 26:152-159.
• [13]Bracke KR, D’hulst AI, Maes T, Moerloose KB, Demedts IK, Lebecque S, Joos GF, Brusselle GG: Cigarette smoke-induced pulmonary inflammation and emphysema are attenuated in CCR6-deficient mice. J Immunol 2006, 177:4350-4359.
• [14]Rackley CR, Stripp BR: Building and maintaining the epithelium of the lung. J Clin Invest 2012, 122:2724-2730.
• [15]Morrisey EE, Cardoso WV, Lane RH, Rabinovitch M, Abman SH, Ai X, Albertine KH, Bland RD, Chapman HA, Checkley W, Epstein JA, Kintner CR, Kumar M, Minoo P, Mariani TJ, McDonald DM, Mukouyama YS, Prince LS, Reese J, Rossant J, Shi W, Sun X, Werb Z, Whitsett JA, Gail D, Blaisdell CJ, Lin QS: Molecular determinants of lung development. Ann Am Thorac Soc 2013, 10:S12-S16.
• [16]Rawlins EL: Lung epithelial progenitor cells: lessons from development. Proc Am Thorac Soc 2008, 5:675-681.
• [17]Reynolds SD, Malkinson AM: Clara cell: progenitor for the bronchiolar epithelium. Int J Biochem Cell Biol 2010, 42:1-4.
• [18]Rock JR, Hogan BL: Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu Rev Cell Dev Biol 2011, 27:493-512.
• [19]Liu H, Ma L, Wu J, Wang K, Chen X: Apoptosis of alveolar wall cells in chronic obstructive pulmonary disease patients with pulmonary emphysema is involved in emphysematous changes. J Huazhong Univ Sci Technolog Med Sci 2009, 29(4):466-469.
• [20]Hodge S, Hodge G, Holmes M, Reynolds PN: Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation. Eur Respir J 2005, 25:447-454.
• [21]Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese RM: In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 1992, 256:1550-1552.
• [22]Rainov NG: A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 2000, 11:2389-2401.
• [23]Semenza GL: HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 2000, 88:1474-1480.
• [24]Rezvani HR, Ali N, Nissen LJ, Harfouche G, de Verneuil H, Taïeb A, Mazurier F: HIF-1α in epidermis: oxygen sensing, cutaneous angiogenesis, cancer, and non-cancer disorders. J Invest Dermatol 2011, 131:1793-1805.
• [25]Yasuo M, Mizuno S, Kraskauskas D, Bogaard HJ, Natarajan R, Cool CD, Zamora M, Voelkel NF: Hypoxia inducible factor-1alpha in human emphysema lung tissue. Eur Respir J 2011, 37:775-783.
• [26]Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH: Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 2007, 117:3810-3820.
• [27]Higgins DF, Kimura K, Iwano M, Haase VH: Hypoxia-inducible factor signaling in the development of tissue fibrosis. Cell Cycle 2008, 7:1128-1132.
• [28]Jaerve A, Bosse F, Müller HW: SDF-1/CXCL12: its role in spinal cord injury. Int J Biochem Cell Biol 2012, 44:452-456.
• [29]Makino H, Aono Y, Azuma M, Kishi M, Yokota Y, Kinoshita K, Takezaki A, Kishi J, Kawano H, Ogawa H, Uehara H, Izumi K, Sone S, Nishioka Y: Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice. J Med Invest 2013, 60:127-137.
• [30]Antoniou KM, Soufla G, Lymbouridou R, Economidou F, Lasithiotaki I, Manousakis M, Drositis I, Spandidos DA, Siafakas NM: Expression analysis of angiogenic growth factors and biological axis CXCL12/CXCR4 axis in idiopathic pulmonary fibrosis. Connect Tissue Res 2010, 51:71-80.
• [31]Auerbach O, Garfnkel L, Hammond EC: Relation of smoking and age to findings in lung parenchyma: a microscopic study. Chest 1974, 65:29-35.
• [32]Papiris SA, Triantafillidou C, Manali ED, Kolilekas L, Baou K, Kagouridis K, Bouros D: Combined pulmonary fibrosis and emphysema. Expert Rev Respir Med 2013, 7:19-31.