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Stella Kourembanas, MD
Neonatologist, Brigham and Women's Hospital
Clement A. Smith Professor of Pediatrics, Harvard Medical School

Brigham and Women's Hospital
Department of Newborn Medicine
75 Francis Street
Boston, MA 02115

Research Email: stella.kourembanas@childrens.harvard.edu

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Research Narrative:

Research Focus

The broad focus of the Kourembanas laboratory is the elucidation of the vascular responses to hypoxia at the molecular, cellular and organismal levels. Hypoxia increases the expression of heme oxygenase-1 (HO-1), a cytoprotective enzyme that degrades heme to generate carbon monoxide (CO, a vasodilating gas with anti-inflammatory properties), biliverdin (which is rapidly converted to the antioxidant bilirubin), and iron (sequestered by ferritin). HO-1 activity protects cells and tissues from hypoxia-induced injury, ischemia-reperfusion and the progression of vascular diseases due to inflammation and oxidative stress. Studies in the laboratory using HO-1 null (-/-) mice and transgenic mice with lung-specific constitutive and inducible HO-1 overexpression support this hypothesis. Whereas hypoxia causes severe pulmonary artery hypertension (PAH) with right ventricular dilatation, oxidative damage and infarction in mice lacking HO-1, mice with high lung HO-1 levels are protected from both lung and cardiac injury. Moreover, wild-type mice exposed to hypoxia develop marked lung inflammation with elevated expression of chemokines and cytokines as well as neutrophil infiltration prior to the manifestation of PAH. Inhibition of early inflammation by transient, inducible, lung-specific expression of HO-1 prevents the later development of PAH. A central line of investigation in the laboratory is the study of the transcriptional and epigenetic mechanisms by which hypoxia induces chemokine gene expression leading to lung inflammation and the mechanisms by which HO-1 activity resolves inflammation and inhibits the prohypertensive actions of hypoxia to maintain vascular homeostasis.

A related area of investigation in the lab is the study of developmental lung injury, a model of bronchopulmonary dysplasia (BPD). BPD is a disease of the preterm infant characterized by a chronic fibroproliferative process associated with inflammation and disruption of normal vessel growth and alveolization. Our studies in animal physiology and basic molecular biology are validated with parallel studies in infants with BPD using patient-derived material. Linked to this work are genomic approaches to identify genetic markers of predisposition to BPD and PAH.

An overarching new area of research in my laboratory explores the role of bone marrow derived stromal cells, also known as mesenchymal stem cells (MSC) in the prevention and treatment of developmental and vascular diseases of the lung, including BPD and PAH. Using several mouse models of lung disease and genetically-modified mice, we have shown that MSC can be isolated, differentiated, transduced and delivered successfully in the in vivo lung. Via paracrine and immunodulatory pathways, MSC can both prevent and reverse lung vascular disease. The molecular and cellular pathways of MSC action is an active area of investigation.

Research Goals

To identify the molecular and cellular basis of lung diseases affecting newborn infants

Outcome/Application of Research

To develop novel therapies for the treatment of newborn lung diseases that currently have  no effective treatment, such as bronchopulmonary dysplasia (BPD).  As we have accomplished with pulmonary hypertension of the newborn whereby, based on studies from our group and others, the use of inhaled nitric oxide has revolutionized the treatment of this formerly highly lethal disorder, we hope to test bone marrow-derived MSC therapeutic approaches to both prevent as well as reverse BPD.


Education:
MD
MD

Other Professional Activities:
Chief, Division of Newborn Medicine, Boston Children's Hospital
NIH Study Section, Standing Member

Publications (Pulled from Harvard Catalyst Profiles):

1. Hudalla H, Michael Z, Christodoulou N, Willis GR, Fernandez-Gonzalez A, Filatava EJ, Dieffenbach P, Fredenburgh LE, Stearman RS, Geraci MW, Kourembanas S, Christou H. Carbonic Anhydrase Inhibition Ameliorates Inflammation and Experimental Pulmonary Hypertension. Am J Respir Cell Mol Biol. 2019 Apr 05.

2. Willis GR, Fernandez-Gonzalez A, Reis M, Mitsialis SA, Kourembanas S. Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension? Int J Mol Sci. 2018 Aug 27; 19(9).

3. Legchenko E, Chouvarine P, Borchert P, Fernandez-Gonzalez A, Snay E, Meier M, Maegel L, Mitsialis SA, Rog-Zielinska EA, Kourembanas S, Jonigk D, Hansmann G. PPAR? agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation. Sci Transl Med. 2018 04 25; 10(438).

4. Mitsialis SA, Willis GR, Fernandez-Gonzalez A, Kourembanas S. Reply to Muraca et al.: Exosome Treatment of Bronchopulmonary Dysplasia: How Pure Should Your Exosome Preparation Be? Am J Respir Crit Care Med. 2018 04 01; 197(7):970.

5. Willis GR, Fernandez-Gonzalez A, Anastas J, Vitali SH, Liu X, Ericsson M, Kwong A, Mitsialis SA, Kourembanas S. Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation. Am J Respir Crit Care Med. 2018 01 01; 197(1):104-116.

6. Christou H, Hudalla H, Michael Z, Filatava EJ, Li J, Zhu M, Possomato-Vieira JS, Dias-Junior C, Kourembanas S, Khalil RA. Impaired Pulmonary Arterial Vasoconstriction and Nitric Oxide-Mediated Relaxation Underlie Severe Pulmonary Hypertension in the Sugen-Hypoxia Rat Model. J Pharmacol Exp Ther. 2018 02; 364(2):258-274.

7. Willis GR, Mitsialis SA, Kourembanas S. "Good things come in small packages": application of exosome-based therapeutics in neonatal lung injury. Pediatr Res. 2018 01; 83(1-2):298-307.

8. Willis GR, Kourembanas S, Mitsialis SA. Toward Exosome-Based Therapeutics: Isolation, Heterogeneity, and Fit-for-Purpose Potency. Front Cardiovasc Med. 2017; 4:63.

9. Thébaud B, Kourembanas S. Can We Cure Bronchopulmonary Dysplasia? J Pediatr. 2017 12; 191:12-14.

10. Willis GR, Kourembanas S, Mitsialis SA. Therapeutic Applications of Extracellular Vesicles: Perspectives from Newborn Medicine. Methods Mol Biol. 2017; 1660:409-432.