Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease.
BACKGROUND
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.


OBJECTIVE
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% O(2)) 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.


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.
Aslam
Muhammad
M
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Baveja
Rajiv
R
Liang
Olin D
OD
Fernandez-Gonzalez
Angeles
A
Lee
Changjin
C
Mitsialis
S Alex
SA
Kourembanas
Stella
S
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology*; D016026:Bone Marrow Transplantation; D018929:Cell Culture Techniques; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D018496:Hyperoxia; D006976:Hypertension, Pulmonary / Q000276:immunology / Q000517:prevention & control; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D055370:Lung Injury / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D011650:Pulmonary Alveoli / Q000276:immunology; D017154:Stromal Cells
D016207:Cytokines