Pneumologie 2014; 68 - A18
DOI: 10.1055/s-0034-1376787

Rescue of function in a cystic fibrosis mouse model by transfer of hematopoetic stem cells

A Munder 1, R Struß 2, A Schambach 2, B Tümmler 1, 3
  • 1Clinic for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover
  • 2Department of Experimental Hematology, Hannover Medical School, Hannover
  • 3Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Member of the German Center for Lung Research (DZL)

Cystic fibrosis (CF) is the most common hereditary disease in the Caucasian population. The disease causing gene CFTR was identified in 1989. So far, more than 1,800 mutations have been identified in the CFTR gene [1], which codes for a cyclic adenosine monophosphate-regulated chloride channel. The malfunction of this channel leads to a progressive loss of function in the CF lung, which is the decisive factor for morbidity and mortality of most CF patients. Beside mucus accumulation in the airways, also an impaired phagocytosis in alveolar macrophages seems to play an important role in the pathogenesis of chronic infection and inflammation in the CF lung [2]. The Gram-negative, ubiquitous opportunistic pathogen Pseudomonas aeruginosa is the key organism in causing CF lung disease.

CF mouse models are an extremely suitable tool to investigate Pseudomonas lung pathogenicity. In our study presented here, we tested whether the increased genetic susceptibility of CF mice to airway infection with P. aeruginosa can be reduced to levels of wild-type mice by transfusion of hematopoietic stem and precursor cells (HPSPCs) of Cftr wildtype mice. Therefore, we subjected recipient B6.CftrT g H ( n e o im ) H g u mice to a lethal dose of irradiation and injected them with hematopoietic progenitor cells from B6 wildtype donor mice. After a six weeks phase of reconstitution mice were infected intratracheally with a disease causing dose of the cytopathic P. aeruginosa strain PAO1. The course of infection was monitored over 144h measuring murine lung function, body weight, rectal temperature and survival of the mice. B6.CftrT g H ( n e o im ) H g u mice which received isogenic HPSPCs served as controls.

References:

[1] Cystic Fibrosis Mutation Database (2014) http://www.genet.sickkids.on.ca/cftr/app Accessed 12 March 2014

[2] Di A, Brown ME, Deriy L V, Li C, Szeto FL1, Chen Y, Huang P, Tong J, Naren AP, Bindokas V, Palfrey HC and Nelson DJ. CFTR regulates phagosome acidification in macrophages and alters bactericidal activity Nat Cell Biol 8, 933 944 (2006)