Effect of adult adipose stem cell therapy in cigarette smoke-induced emphysema

1. Effect of adult adipose stem cell therapy in cigarette smoke-induced emphysema Irina Petrache, Kelly S. Schweitzer, Brian H. Johnstone, Dmitry Traktuev, Jana Garrison, Natalia I. Rush, Jeremy J. Adamowicz, Mary Van Demark, Amanda Fisher, Todd G. Cook, Dongni Feng, Stephanie Merfeld-Clauss, Krzysztof Kamocki, Robert G. Presson, Hal Broxmeyer, and Keith L. March IUPUI Signature Center The Krannert Center Indiana University Dept of Medicine, Division of Pulmonary and Critical Care Medicine and Division of Cardiology Funding: IU Signature Center

2. COPD is the fourth leading cause of death in the US and worldwide (>2.7 million deaths/ yr) Chronic bronchitis Emphysema Emphysema = permanent destruction of airspaces distal to the terminal bronchioles with loss of the alveolar unit ANTI-PROTEASES CELL REPAIR/ PROLIFERATION Smoking Alpha-1 antitrypsin deficiency PROTEASES VEGF inhibition CELL DEATH Excessive lung endothelial apoptosis Kasahara et al, JCI 00 Petrache et al, Nat Med 05 Giordano et al, JBC 08.

4. Relevance of the VEGFR blockade-induced emphysema : Vascular hypothesis resurrected: Liebow, 1957

5. Adult Adipose Stem Cells (ASC) • Angiogenic and anti-apoptotic potential, stabilize blood vessels Rehman J et al, Circulation 04 Traktuev D et al, Circ Res 08 Cai L et al, Stem Cells 07

6. Hypothesis • Treatment with ASC will prevent alveolar endothelial cell death and/or accelerate the repair of alveolar tissue in the setting of cigarette smoke-induced lung injury. • ASC treatment will prevent the development of cigarette smoke-induced experimental emphysema.

7. Method • ASC isolated from adult littermate mice and propagated in culture. • ASC delivered systemically to mice exposed to cigarette smoking. Cig smoke exposure (4 months) ASC treatment (2 mo)

8. Lung homing following intravenous treatment with ASC

9. ASC reduced the number of inflammatory cells in the bronchoalveolar lavage of cigarette smoke-exposed mice (4 months) * * * Cells / ml Ctl Ctl Cig Smoke Cig Smoke Cig Smk + ASC Cig Smk + ASC

10. Control ASC inhibited the development of cigarette smoke- induced alveolar space enlargement in mice *p=0.03 Cigarette Smoke (4 mo) Cig Smk + ASC Veh ASC Veh ASC Ctl Cig smk

11. ASC restored the body weight of mice chronically exposed to cigarette smoke-

12. ASC rescued cigarette smoke- induced BM progenitor cell dysfunction in mice

13. Summary (American Journal of Respiratory and Critical Care Medicine, 2010, in press) • ASC decreased cigarette smoke-induced lung apoptosis and inflammation • ASC treatment inhibited the development of airspace enlargement in the cigarette smoke model of murine emphysema • ASC had remarkable effects on restoring systemic toxic effects of CS on body weight and BM progenitor cell function • The mechanism by which ASC protect the lung from cigarette smoke injury remains to be investigated.

14. Conclusions • Adipose-derived stem cells may be a therapeutic option for cigarette smoke-induced disease in both the lungs and other organs. • Our data predict beneficial effects of ASC on other lung and systemic disorders that share pathogenic elements with those of emphysema, such as acute lung injury and pulmonary hypertension, or on conditions of untreatable weight loss or bone marrow suppression.