Mesenchymal Stem Cells Restore Lung Function by Recruiting Resident and Nonresident Proteins
0963-6897/11 $90.00 + .00 DOI: http://dx.doi.org/10.3727/096368910X557254 E-ISSN 1555-3892 www.cognizantcommunication.com
Philipp Jungebluth,* Mark Luedde,† Elisabet Ferrer,‡ Tom Luedde,§ Mihael Vucur,§ Victor I. Peinado,‡ Tetsuhiko Go,¶ Catharina Schreiber,# Maximilian von Richthofen,# Augustinus Bader,# Johannes Haag,# Kai H. Darsow,# Sebastian J. Bartel,# Harald A. Lange,# Dario Furlani,** Gustav Steinhoff,** and Paolo Macchiarini*
*Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden †Department of Cardiology, University of Kiel, Kiel, Germany
‡Hospital Clinic, University of Barcelona, Barcelona, Spain
§Department of Gastroenterology, University Hospital Aachen, Aachen, Germany
¶Department of General Thoracic and Breast-Endcrinological Surgery, Kagawa University Miki-Cho, Kagawa, Japan #Biomedical-Biotechnological Center, Leipzig, Leipzig, Germany
**Department of Cardiac Surgery, University Rostock, Rostock, Germany
Chronic thromboembolic pulmonary hypertension (CTEPH) has emerged as one of the leading causes of severe pulmonary hypertension (PH). It is characterized by single or recurrent unresolved pulmonary thromboemboli obstructing and/or obliterating the pulmonary vascular bed. Pulmonary embolism is, however, thought to be the initiating event followed by progressive pulmo- nary vascular remodeling. This leads to elevation of pul- monary vascular resistance, progressive pulmonary hy- pertension, and right ventricular failure and death. Although it has been investigated for years, the exact mechanisms influencing its etiopathology and outcome are still poorly understood (24,30,36,40). Vascular dis- obliteration by pulmonary endarterectomy (PEA) is the preferred treatment but not all patients are eligible for surgery (11–13,15,21). Other therapeutic alternatives include lung transplantation and balloon pulmonary angioplasty (7,16). Clinical evidence regarding pharmacologic strategy is currently restricted to small, uncontrolled trials with, at most, a moderate outcome (12). The tissue engineering, which is currently applied in several studies, might be the wrong method to design such a highly complex and multifunctional organ like the lung when targeting the clinical application. Cell-based therapy, latterly used in experimental studies (38,45), might be a more promising therapeutic option for lung diseases and the treatment of CTEPH. The potential role of mesenchymal stem cells (MSCs) as a treatment for CTEPH has not been previously studied. Bone marrow-derived MSCs are so-called multipotent adult stem cells. They have the ability to differentiate into various cell types (5,32,34). When engrafting into the lung they can differentiate into type I and II epithelial cells and fibroblasts. Other lung injury models demonstrated an improvement after MSC administration (27,35) and this was explained not only by their tissue incorporation but also their immunomodulatory capability (1) and paracrine signaling.
We now demonstrate that intratracheal MSC administration in our previously established experimental animal model of CTPEH (14) results in a restoration of both lung and liver tissue and a significant improvement of all clinical parameters. These remarkable changes might be explained via the altered protein expression level.
The findings of the current study demonstrate that the IT application of MSCs in an animal model of CTEPH is highly effective and led to a significant restoration of lung tissue as demonstrated by the amelioration of all relevant parameters. The MSC administration resulted in a significant change of lung tissue protein expression profile, and this might be mediated by both contact dependent and independent mechanisms. We showed the multipotency of MSC after intratracheal application by their expressed and/or recruited proteins. The effective meaning of these lung tissue foreign proteins concerning the outcome and the developing of the CTEPH has to be elucidated. There might be a supposable necessity of adding differentiating/growth factors to induce and support cell differentiation into the target tissue. The here described method is easy and safe to apply even in severe health conditions, which makes it highly potential for the clinical use as a treatment in patients suffering from CTEPH.