Pulmonary hypertension (PHtn) is a life-threatening condition that can affect all ages, from neonates to adults. The hallmark of this disorder is increased pulmonary arteriolar vasoconstriction and vessel wall remodeling characterized by intimal hyperplasia, excess smooth muscle cell layers in the media, and deposition of extracellular matrix. Although the survival and quality of life has improved in patients with pulmonary hypertension, there is no cure for this disease. The mainstay of current medical treatment falls into several forms of therapy, including the use of vasodilators, anti-coagulants, anti-platelet agents, anti- inflammatory and vascular-remodeling therapies. Hypoxia is a known primary or secondary stimulus for the development of PHtn and various animal models exposed to hypoxia develop the pulmonary and cardiac manifestations that are characteristic of human disease. We have investigated the therapeutic potential of treating hypoxia-induced PHtn with genetically-engineered bone marrow-derived mesenchymal stem cells (MSC) expressing the cytoprotective gene, heme oxygenase-1 (HO-1). Using a mouse model of hypoxia- induced pulmonary hypertension that we and others have characterized, we had previously reported that transgenic mice with lung-specific overexpression of HO-1 driven by the surfactant protein C (SPC) promoter (SHO1) do not develop PHtn in response to hypoxic exposure. Mice deficient in HO-1 have a maladaptive response to hypoxia and in addition to pulmonary hypertension, they develop right ventricular dilatation and infarction compared to wild type animals. We have generated preliminary data showing that transplantation of MSC over-expressing HO-1 via the jugular vein into the lung could reverse hypoxia-induced PHtn in mice deficient in HO-1. Our overall goal is to understand the mechanisms by which MSC inhibit /reverse the development of pulmonary hypertension in the hypoxic mouse model so that we can develop rational therapies for the treatment of this disease in humans.
The specific aims of the proposal are: (1) to investigate whether HO-1 is required for the protective action of MSC on the development of pulmonary hypertension, (2) to investigate the mechanisms of MSC homing and engraftment in the lung, and (3) to investigate the basis of MSC repair mechanisms in the hypoxic lung.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085446-04
Application #
7790607
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$422,500
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Willis, Gareth R; Kourembanas, Stella; Mitsialis, S Alex (2017) Toward Exosome-Based Therapeutics: Isolation, Heterogeneity, and Fit-for-Purpose Potency. Front Cardiovasc Med 4:63
Willis, Gareth R; Mitsialis, S Alex; Kourembanas, Stella (2017) ""Good things come in small packages"": application of exosome-based therapeutics in neonatal lung injury. Pediatr Res :
Mitsialis, S Alex; Kourembanas, Stella (2016) Stem cell-based therapies for the newborn lung and brain: Possibilities and challenges. Semin Perinatol 40:138-51
Kourembanas, Stella (2014) Expanding the pool of stem cell therapy for lung growth and repair. Circulation 129:2091-3
Hale, Andrew; Lee, Changjin; Annis, Sofia et al. (2014) An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells. Biochim Biophys Acta 1843:2528-42
Xiao, Yongguang; Christou, Helen; Liu, Li et al. (2013) Endothelial indoleamine 2,3-dioxygenase protects against development of pulmonary hypertension. Am J Respir Crit Care Med 188:482-91
Anversa, Piero; Perrella, Mark A; Kourembanas, Stella et al. (2012) Regenerative pulmonary medicine: potential and promise, pitfalls and challenges. Eur J Clin Invest 42:900-13
Hansmann, Georg; Fernandez-Gonzalez, Angeles; Aslam, Muhammad et al. (2012) Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ 2:170-81
Fernandez-Gonzalez, Angeles; Alex Mitsialis, S; Liu, Xianlan et al. (2012) Vasculoprotective effects of heme oxygenase-1 in a murine model of hyperoxia-induced bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 302:L775-84
Lee, Changjin; Mitsialis, S Alex; Aslam, Muhammad et al. (2012) Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 126:2601-11

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