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Tissue-Specific Stem Cells
Version of Record online: 28 JAN 2011
Copyright © 2010 AlphaMed Press
Volume 29, Issue 1, pages 99–107, January 2011
How to Cite
Liang, O. D., Mitsialis, S. A., Chang, M. S., Vergadi, E., Lee, C., Aslam, M., Fernandez-Gonzalez, A., Liu, X., Baveja, R. and Kourembanas, S. (2011), Mesenchymal Stromal Cells Expressing Heme Oxygenase-1 Reverse Pulmonary Hypertension. STEM CELLS, 29: 99–107. doi: 10.1002/stem.548
Author contributions: O.D.L.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; S.A.M.: conception and design, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, manuscript writing; M.S.C.: collection and/or assembly of data; E.V.: collection and/or assembly of data; C.L.: collection and/or assembly of data; M.A.: collection and/or assembly of data; A.F.-G.: collection and/or assembly of data, X.L.: provision of study material or patients; R.B.: provision of study material or patients; S.K.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.
First published online in STEM CELLS EXPRESS October 18, 2010.
Disclosure of potential conflicts of interest is found at the end of this article.
- Issue online: 28 JAN 2011
- Version of Record online: 28 JAN 2011
- Accepted manuscript online: 18 OCT 2010 01:53PM EST
- Manuscript Accepted: 30 SEP 2010
- Manuscript Received: 15 JUL 2010
- Mesenchymal stem cell;
- Transgenic mouse
Pulmonary arterial hypertension (PAH) remains a serious disease, and although current treatments may prolong and improve quality of life, search for novel and effective therapies is warranted. Using genetically modified mouse lines, we tested the ability of bone marrow-derived stromal cells (mesenchymal stem cells [MSCs]) to treat chronic hypoxia-induced PAH. Recipient mice were exposed for 5 weeks to normobaric hypoxia (8%–10% O2), MSC preparations were delivered through jugular vein injection and their effect on PAH was assessed after two additional weeks in hypoxia. Donor MSCs derived from wild-type (WT) mice or heme oxygenase-1 (HO-1) null mice (Hmox1KO) conferred partial protection from PAH when transplanted into WT or Hmox1KO recipients, whereas treatment with MSCs isolated from transgenic mice harboring a human HO-1 transgene under the control of surfactant protein C promoter (SH01 line) reversed established disease in WT recipients. SH01-MSC treatment of Hmox1KO animals, which develop right ventricular (RV) infarction under prolonged hypoxia, resulted in normal RV systolic pressure, significant reduction of RV hypertrophy and prevention of RV infarction. Donor MSCs isolated from a bitransgenic mouse line with doxycycline-inducible, lung-specific expression of HO-1 exhibited similar therapeutic efficacy only on doxycycline treatment of the recipients. In vitro experiments indicate that potential mechanisms of MSC action include modulation of hypoxia-induced lung inflammation and inhibition of smooth muscle cell proliferation. Cumulatively, our results demonstrate that MSCs ameliorate chronic hypoxia-induced PAH and their efficacy is highly augmented by lung-specific HO-1 expression in the transplanted cells, suggesting an interplay between HO-1-dependent and HO-1-independent protective pathways. STEM CELLS 2011;29:99–107