Advertisement

Mesenchymal Stem Cells: Complex Players in Lung Repair and Injury

  • Mauricio Rojas
  • Naveen Gupta
  • Susan M. Majka
Chapter
Part of the Stem Cells and Cancer Stem Cells book series (STEM, volume 7)

Abstract

In the past decade, investigations related to the role of mesenchymal stem cells, both bone marrow derived and local, in lung disease and repair have grown exponentially. Stem cells are emerging as a therapeutic modality in various inflammatory disease states. A number of ongoing randomized phase I/II clinical trials are evaluating the effects of allogeneic mesenchymal stem cell (MSC) infusion in patients with multiple sclerosis, graft-versus-host disease, Crohn’s disease, and severe, chronic myocardial ischemia. MSC are also being considered and tested in clinical trials as a potential therapy in patients with inflammatory lung diseases including pulmonary fibrosis, acute lung injury, chronic obstructive pulmonary disease and emphysema. Several studies, including our own, have demonstrated compelling benefits from the administration of bone marrow derived MSC in animal models of lung injury. These studies are leading to growing interest in the therapeutic use of MSCs in lung diseases. In this chapter, we describe how the immunoregulatory effects of MSCs can confer substantial protection in the setting of the most common lung diseases such as fibrosis, acute lung injury, chronic obstructive pulmonary disease, asthma, and lung transplant. In addition we will discuss recent evidence for resident lung MSC and their functions during tissue homeostasis and disease.

Keywords

Chronic Obstructive Pulmonary Disease Mesenchymal Stem Cell Pulmonary Arterial Hypertension Idiopathic Pulmonary Fibrosis Bronchoalveolar Lavage Fluid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Badri L, Murray S, Liu LX, Walker NM, Flint A, Wadhwa A, Chan KM, Toews GB, Pinsky DJ, Martinez FJ et al (2011) Mesenchymal stromal cells in bronchoalveolar lavage as predictors of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 183:1062–1070PubMedCentralPubMedCrossRefGoogle Scholar
  2. Beltrami AP, Cesselli D, Bergamin N, Marcon P, Rigo S, Puppato E, D’Aurizio F, Verardo R, Piazza S, Pignatelli A et al (2007) Multipotent cells can be generated in vitro from several adult human organs (heart, liver, and bone marrow). Blood 110:3438–3446PubMedCrossRefGoogle Scholar
  3. Crisan M, Yap S, Casteilla L, Chen C-W, Corselli M, Park TS, Andsriolo G, Sun B, Zheng B, Zhang L et al (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313PubMedCrossRefGoogle Scholar
  4. Grove DA, Xu J, Joodi R, Torres-Gonzales E, Neujahr D, Mora AL, Rojas M (2011) Attenuation of early airway obstruction by mesenchymal stem cells in a murine model of heterotopic tracheal transplantation. J Heart Lung Transplant 30:341–350PubMedCentralPubMedCrossRefGoogle Scholar
  5. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA (2007) Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 179:1855–1863PubMedCrossRefGoogle Scholar
  6. Gupta N, Krasnodembskaya A, Kapetanaki M, Mouded M, Tan X, Serikov V, Matthay MA (2012) Mesenchymal stem cells enhance survival and bacterial clearance in murine E. coli pneumonia. Thorax (ePub)Google Scholar
  7. Hennrick KT, Keeton AG, Nanua S, Kijek TG, Goldsmith AM, Sajjan US, Bentley JK, Lama VN, Moore BB, Schumacher RE et al (2007) Lung cells from neonates show a mesenchymal stem cell phenotype. Am J Respir Crit Care Med 175:1158–1164PubMedCrossRefGoogle Scholar
  8. Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford TJ, Toews GB, Pinsky DJ, Peters-Golden M, Lama VN (2008) Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol 181:4389–4396PubMedCentralPubMedCrossRefGoogle Scholar
  9. Jiang Y, Vaessen B, Lenvik T, Blackstad M, Reyes M, Verfaillie CM (2002) Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp Hematol 30:896–904PubMedCrossRefGoogle Scholar
  10. Jun D, Garat C, West J, Thorn N, Chow K, Cleaver T, Sullivan T, Torchia EC, Childs C, Shade T et al (2011) The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferation. Stem Cells 29:725–735PubMedCentralPubMedCrossRefGoogle Scholar
  11. Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee JW, Matthay MA (2010) Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells 28:2229–2238PubMedCentralPubMedCrossRefGoogle Scholar
  12. Lama VN, Smith L, Badri L, Flint A, Andrei A-C, Murray S, Wang Z, Liao H, Toews GB, Krebsbach PH et al (2007) Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest 117:989–996PubMedCentralPubMedCrossRefGoogle Scholar
  13. Lee JW, Fang X, Gupta N, Serikov V, Matthay MA (2009a) Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci USA 106:16357–16362PubMedCentralPubMedCrossRefGoogle Scholar
  14. Lee JW, Gupta N, Serikov V, Matthay MA (2009b) Potential application of mesenchymal stem cells in acute lung injury. Expert Opin Biol Ther 9:1259–1270PubMedCentralPubMedCrossRefGoogle Scholar
  15. Liebler JM, Lutzko C, Banfalvi A, Senadheera D, Aghamohammadi N, Crandall ED, Borok Z (2008) Retention of human bone marrow-derived cells in murine lungs following bleomycin-induced lung injury. Am J Physiol Lung Cell Mol Physiol 295:L285–L292PubMedCentralPubMedCrossRefGoogle Scholar
  16. Martin J, Helm K, Ruegg P, Varella-Garcia M, Burnham E, Majka S (2008) Adult lung side population cells have mesenchymal stem cell potential. Cytotherapy 10:140–151PubMedCrossRefGoogle Scholar
  17. Masoli M, Fabian D, Holt S, Beasley R (2004) The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59:469–478PubMedCrossRefGoogle Scholar
  18. Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, Liles WC, Stewart DJ (2010) Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 182:1047–1057PubMedCrossRefGoogle Scholar
  19. Méndez-Ferrer SMT, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma’ayan A, Enikolopov GN, Frenette PS (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466:829–834PubMedCentralPubMedCrossRefGoogle Scholar
  20. Murray CJ, Lopez AD (1997) Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 349:1498–1504PubMedCrossRefGoogle Scholar
  21. Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15:42–49PubMedCentralPubMedCrossRefGoogle Scholar
  22. Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG (2003) Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 100:8407–8411PubMedCentralPubMedCrossRefGoogle Scholar
  23. Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG (2007) Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA 104:11002–11007PubMedCentralPubMedCrossRefGoogle Scholar
  24. Postma DS, Timens W (2006) Remodeling in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 3:434–439PubMedCrossRefGoogle Scholar
  25. Ribeiro-Paes JT, Bilaqui A, Greco OT, Ruiz MA, Marcelino MY, Stessuk T, de Faria CA, Lago MR (2011) Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema. Int J Chron Obstruct Pulmon Dis 6:63–71PubMedCentralPubMedCrossRefGoogle Scholar
  26. Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, Brigham KL (2005) Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 33:145–152PubMedCentralPubMedCrossRefGoogle Scholar
  27. Summer R, Fitzsimmons K, Dwyer D, Murphy J, Fine A (2007) Isolation of an adult mouse lung mesenchymal progenitor cell population. Am J Respir Cell Mol Biol 37:152–159PubMedCentralPubMedCrossRefGoogle Scholar
  28. Walker NM, Badri LN, Wadhwa A, Wettlaufer S, Peters-Golden M, Lama VN (2012) Prostaglandin E2 as an inhibitory modulator of fibrogenesis in human lung allografts. Am J Respir Crit Care Med 185:77–84CrossRefGoogle Scholar
  29. Weiss DJ, Kolls JK, Ortiz LA, Panoskaltsis-Mortari A, Prockop DJ (2008) Stem cells and cell therapies in lung biology and lung diseases. Proc Am Thorac Soc 5:637–667PubMedCentralPubMedCrossRefGoogle Scholar
  30. Xu J, Gonzalez ET, Iyer SS, Mac V, Mora AL, Sutliff RL, Reed A, Brigham KL, Kelly P, Rojas M (2009) Use of senescence-accelerated mouse model in bleomycin-induced lung injury suggests that bone marrow derived cells can alter the outcome of lung injury in aged mice. J Gerontol A Biol Sci Med Sci 64A:731–739PubMedCentralCrossRefGoogle Scholar
  31. Yan X, Liu Y, Han Q, Jia M, Liao L, Qi M, Zhao RC (2007) Injured microenvironment directly guides the differentiation of engrafted Flk-1(+) mesenchymal stem cell in lung. Exp Hematol 35:1466–1475PubMedCrossRefGoogle Scholar
  32. Zhen G, Liu H, Gu N, Zhang H, Xu Y, Zhang Z (2008) Mesenchymal stem cells transplantation protects against rat pulmonary emphysema. Front Biosci 13:3415–3422PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  1. 1.Gates Center for Regenerative Medicine and Stem Cell BiologyUniversity of Colorado Health Science CenterAuroraUSA

Personalised recommendations