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Bone Marrow Stromal Cells Attenuate Lung Injury in a Murine Model of Neonatal Chronic Lung Disease

¹ Department of Pediatrics, Harvard Medical School and Division of Newborn Medicine, Children's Hospital Boston, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Stella Kourembanas, M.D., Division of Newborn Medicine, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. E-mail: stella.kourembanas{at}childrens.harvard.edu

Rationale: Neonatal chronic lung disease, known as bronchopulmonary dysplasia (BPD), remains a serious complication of prematurity despite advances in the treatment of extremely low birth weight infants.

Objectives: Given the reported protective actions of bone marrow stromal cells (BMSCs; mesenchymal stem cells) in models of lung and cardiovascular injury, we tested their therapeutic potential in a murine model of BPD.

Methods: Neonatal mice exposed to hyperoxia (75% O₂) were injected intravenously on Day 4 with either BMSCs or BMSC-conditioned media (CM) and assessed on Day 14 for lung morphometry, vascular changes associated with pulmonary hypertension, and lung cytokine profile.

Measurements and Main Results: Injection of BMSCs but not pulmonary artery smooth muscle cells (PASMCs) reduced alveolar loss and lung inflammation, and prevented pulmonary hypertension. Although more donor BMSCs engrafted in hyperoxic lungs compared with normoxic controls, the overall low numbers suggest protective mechanisms other than direct tissue repair. Injection of BMSC-CM had a more pronounced effect than BMSCs, preventing both vessel remodeling and alveolar injury. Treated animals had normal alveolar numbers at Day 14 of hyperoxia and a drastically reduced lung neutrophil and macrophage accumulation compared with PASMC–CM-treated controls. Macrophage stimulating factor 1 and osteopontin, both present at high levels in BMSC-CM, may be involved in this immunomodulation.

Conclusions: BMSCs act in a paracrine manner via the release of immunomodulatory factors to ameliorate the parenchymal and vascular injury of BPD in vivo. Our study suggests that BMSCs and factor(s) they secrete offer new therapeutic approaches for lung diseases currently lacking effective treatment.

Key Words: bronchopulmonary dysplasia • pulmonary hypertension • mesenchymal stem cells • inflammation • bone marrow stromal cells

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Bone marrow stromal cells (BMSCs) have cytoprotective effects in adult animal models of lung injury through poorly-defined mechanisms, which may include modulation of lung inflammation. Whether BMSC therapy can attenuate lung injury in a neonatal mouse model of bronchopulmonary dysplasia and the potential mechanisms of action are unknown. What This Study Adds to the Field Systemic delivery of BMSC-conditioned media inhibits lung inflammation and prevents neonatal lung injury due to hyperoxia, suggesting that these effects are mediated through paracrine mechanisms.

 

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				S. H. Abman and M. A. Matthay Mesenchymal Stem Cells for the Prevention of Bronchopulmonary Dysplasia: Delivering the Secretome Am. J. Respir. Crit. Care Med., December 1, 2009; 180(11): 1039 - 1041. [Full Text] [PDF]