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% 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. 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.
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% 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. 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.
Authors: Mauricio Rojas; Jianguo Xu; Charles R Woods; Ana L Mora; Willy Spears; Jesse Roman; Kenneth L Brigham Journal: Am J Respir Cell Mol Biol Date: 2005-05-12 Impact factor: 6.914
Authors: Jeffrey L Spees; Mandolin J Whitney; Deborah E Sullivan; Joseph A Lasky; Miguel Laboy; Joni Ylostalo; Darwin J Prockop Journal: FASEB J Date: 2007-11-21 Impact factor: 5.191
Authors: Jalees Rehman; Dmitry Traktuev; Jingling Li; Stephanie Merfeld-Clauss; Constance J Temm-Grove; Jason E Bovenkerk; Carrie L Pell; Brian H Johnstone; Robert V Considine; Keith L March Journal: Circulation Date: 2004-03-01 Impact factor: 29.690
Authors: Luis A Ortiz; Frederica Gambelli; Christine McBride; Dina Gaupp; Melody Baddoo; Naftali Kaminski; Donald G Phinney Journal: Proc Natl Acad Sci U S A Date: 2003-06-18 Impact factor: 12.779
Authors: Biju Parekkadan; Daan van Poll; Kazuhiro Suganuma; Edward A Carter; François Berthiaume; Arno W Tilles; Martin L Yarmush Journal: PLoS One Date: 2007-09-26 Impact factor: 3.240
Authors: Michael A Matthay; B Taylor Thompson; Elizabeth J Read; David H McKenna; Kathleen D Liu; Carolyn S Calfee; Jae Woo Lee Journal: Chest Date: 2010-10 Impact factor: 9.410
Authors: Anne Hilgendorff; Irwin Reiss; Harald Ehrhardt; Oliver Eickelberg; Cristina M Alvira Journal: Am J Respir Cell Mol Biol Date: 2014-02 Impact factor: 6.914
Authors: Sara K Berkelhamer; Gina A Kim; Josiah E Radder; Stephen Wedgwood; Lyubov Czech; Robin H Steinhorn; Paul T Schumacker Journal: Free Radic Biol Med Date: 2013-03-14 Impact factor: 7.376