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Newborn Medicine Research

Research Overview

Molecular biology of oxygen-induced lung injury and protective/repair mechanisms. 
The pulmonary vasculature monitors and actively responds to changes in oxygen tension and associated changes in the intracellular levels of reactive oxygen intermediates. Such signals trigger gene expression cascades that play profound roles in vascular wall remodeling, vascular tone, and inflammatory processes, as exemplified by hypoxia-induced pulmonary hypertension. Dr. Mitsialis' laboratory has developed a number of animal models of experimental pulmonary hypertension based on genetically-modified mice and utilize them to understand the molecular basis of this disease. They are particularly interested in deciphering, at the molecular level, the pivotal signals that commit the vasculature towards a pathologic state, and how self-defense mechanisms, such as the action of cytoprotective genes or the activation of bone-marrow derived or lung-resident stem cells, can prevent or reverse the disease process.

Polymorphisms of cytoprotective genes and genomics of lung disease. 
The inducible isoform of Heme Oxygenase (HO-1) has been established as a crucial cytoprotective gene in a number of animal models. Recent clinical studies have associated genetic polymorphisms in transcriptional regulatory regions of the human HO-1 gene with protection from cardiovascular disease. Dr. Mitsialis' laboratory is characterizing the molecular mechanisms regulating human HO-1 basal expression and inducibility in response to diverse stress stimuli, by defining the impact of known polymorphisms on the composition and function of the HO-1 gene promoter transcriptional complexes. In parallel, they are screening a patient population for possible linkage of HO-1 regulatory polymorphisms, as well as genetic variants of other candidate genes, to the development of pulmonary diseases, in particular bronchopulmonary dysplasia (BPD), the most prevalent long-term complication of prematurity.

Respiratory epithelium function in airway disease. 
Ciliopathies underlie a wide spectrum of human genetic disorders, with both adult and developmental phenotypes. The prototype ciliopathy, Primary Ciliary Dyskinesia (PCD), is a genetically heterogeneous disorder. Patients exhibit varying degrees of clinical severity, manifested by development of bronchiectasis, inflammation, and development of features characteristic of chronic lung disease (COPD), the severity of lung disease being directly associated with the extent of loss of ciliary function in the affected epithelium. Dr. Mitsialis' laboratory has developed a novel animal model of PCD, based on the demonstration that ablation of a previously uncharacterized murine gene can result in severe defects in respiratory cilia structure and function. They are defining the molecular mechanisms through which this genetic lesion affects ciliary motility and lung epithelium integrity. In addition, they are establishing the framework for the development of tools to genetically screen human PCD cases of unknown etiology for putative mutations in this novel locus.

Research Background

Director, Animal Models of Lung Diseases, Division of Newborn Medicine

Education

1974B.A., Biochemistry, Princeton University

1983Ph.D., Microbiology, Columbia University

1986Postdoctoral Fellowship in Developmental Biology, Harvard University

Memberships

American Heart Association, Basic Science Council

American Thoracic Society

Honors and Awards

CRC Freshman Chemistry Achievement Award; Tau Alpha Pi Honor Society; Princeton University Scholarship; National Science Foundation Traineeship; Scholar, Anglo-American-Hellenic Bureau of Education; University Fellow, College of Physicians & Surgeons, Columbia University; NIH and American Cancer Society Postdoctoral Fellowships; Medical Foundation Fellowship; NIH F.I.R.S.T. Award

Selected Publications

  1. Fredenburgh LE, Perrella MA, Mitsialis SA. The role of heme oxygenase-1 in pulmonary disease. Am J. Respir. Cell Mol. Biol. 2007;36:158-165.
     
  2. Fernandez-Gonzalez A, Kourembanas S, Wyatt TA, Mitsialis SA. Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype. Am J. Respir. Cell Mol. Biol. 2009;40:305-313.
     
  3. Aslam M, Baveja R, Liang OD, Fernandez-Gonzalez A, Lee C, Mitsialis SA, Kourembanas S. Bone marrow stromal cells attenuate lung injury in a murin

Publications

  1. Immunoregulatory Macrophages Modify Local Pulmonary Immunity and Ameliorate Hypoxic Pulmonary Hypertension. Arterioscler Thromb Vasc Biol. 2024 Dec; 44(12):e288-e303. View Abstract
  2. Mesenchymal stromal cell extracellular vesicles improve lung development in mechanically ventilated preterm lambs. Am J Physiol Lung Cell Mol Physiol. 2024 Jun 01; 326(6):L770-L785. View Abstract
  3. SOCS3 regulates pathological retinal angiogenesis through modulating SPP1 expression in microglia and macrophages. Mol Ther. 2024 May 01; 32(5):1425-1444. View Abstract
  4. Photoreceptors inhibit pathological retinal angiogenesis through transcriptional regulation of Adam17 via c-Fos. Angiogenesis. 2024 Aug; 27(3):379-395. View Abstract
  5. Immunoregulatory macrophages modify local pulmonary immunity and ameliorate hypoxic-pulmonary hypertension. bioRxiv. 2023 Aug 02. View Abstract
  6. Harnessing the therapeutic potential of the stem cell secretome in neonatal diseases. Semin Perinatol. 2023 04; 47(3):151730. View Abstract
  7. Mesenchymal Stromal/Stem Cell Extracellular Vesicles and Perinatal Injury: One Formula for Many Diseases. Stem Cells. 2022 11 29; 40(11):991-1007. View Abstract
  8. Antenatal Mesenchymal Stromal Cell Extracellular Vesicle Therapy Prevents Preeclamptic Lung Injury in Mice. Am J Respir Cell Mol Biol. 2022 01; 66(1):86-95. View Abstract
  9. Extracellular Vesicles Protect the Neonatal Lung from Hyperoxic Injury through the Epigenetic and Transcriptomic Reprogramming of Myeloid Cells. Am J Respir Crit Care Med. 2021 12 15; 204(12):1418-1432. View Abstract
  10. Antenatal mesenchymal stromal cell extracellular vesicle treatment preserves lung development in a model of bronchopulmonary dysplasia due to chorioamnionitis. Am J Physiol Lung Cell Mol Physiol. 2022 02 01; 322(2):L179-L190. View Abstract
  11. Intratracheal transplantation of trophoblast stem cells attenuates acute lung injury in mice. Stem Cell Res Ther. 2021 08 30; 12(1):487. View Abstract
  12. Mesenchymal stromal cell-derived syndecan-2 regulates the immune response during sepsis to foster bacterial clearance and resolution of inflammation. FEBS J. 2022 01; 289(2):417-435. View Abstract
  13. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Restore Thymic Architecture and T Cell Function Disrupted by Neonatal Hyperoxia. Front Immunol. 2021; 12:640595. View Abstract
  14. Therapeutic Effects of Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles in Oxygen-Induced Multi-Organ Disease: A Developmental Perspective. Front Cell Dev Biol. 2021; 9:647025. View Abstract
  15. Mesenchymal stromal cell-derived extracellular vesicle therapy prevents preeclamptic physiology through intrauterine immunomodulation†. Biol Reprod. 2021 02 11; 104(2):457-467. View Abstract
  16. Mesenchymal stromal cell-derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia-induced lung injury. J Extracell Vesicles. 2020 Jul 13; 9(1):1790874. View Abstract
  17. International Society for Extracellular Vesicles and International Society for Cell and Gene Therapy statement on extracellular vesicles from mesenchymal stromal cells and other cells: considerations for potential therapeutic agents to suppress coronavirus disease-19. Cytotherapy. 2020 09; 22(9):482-485. View Abstract
  18. The Unsettling Ambiguity of Therapeutic Extracellular Vesicles from Mesenchymal Stromal Cells. Am J Respir Cell Mol Biol. 2020 05; 62(5):539-540. View Abstract
  19. Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes. JCI Insight. 2019 11 01; 4(21). View Abstract
  20. Heme oxygenase-1 dampens the macrophage sterile inflammasome response and regulates its components in the hypoxic lung. Am J Physiol Lung Cell Mol Physiol. 2020 01 01; 318(1):L125-L134. View Abstract
  21. Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles. 2019; 8(1):1609206. View Abstract
  22. Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension? Int J Mol Sci. 2018 Aug 27; 19(9). View Abstract
  23. PPAR? agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation. Sci Transl Med. 2018 04 25; 10(438). View Abstract
  24. 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. View Abstract
  25. 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. View Abstract
  26. "Good things come in small packages": application of exosome-based therapeutics in neonatal lung injury. Pediatr Res. 2018 01; 83(1-2):298-307. View Abstract
  27. Toward Exosome-Based Therapeutics: Isolation, Heterogeneity, and Fit-for-Purpose Potency. Front Cardiovasc Med. 2017; 4:63. View Abstract
  28. Therapeutic Applications of Extracellular Vesicles: Perspectives from Newborn Medicine. Methods Mol Biol. 2017; 1660:409-432. View Abstract
  29. Stem cell-based therapies for the newborn lung and brain: Possibilities and challenges. Semin Perinatol. 2016 Apr; 40(3):138-51. View Abstract
  30. Systemic Administration of Human Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles Ameliorates Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation in Immunocompetent Mice. Stem Cells Transl Med. 2015 Nov; 4(11):1302-16. View Abstract
  31. The Sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up. Pulm Circ. 2014 Dec; 4(4):619-29. View Abstract
  32. An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells. Biochim Biophys Acta. 2014 Nov; 1843(11):2528-42. View Abstract
  33. Endothelial indoleamine 2,3-dioxygenase protects against development of pulmonary hypertension. Am J Respir Crit Care Med. 2013 Aug 15; 188(4):482-91. View Abstract
  34. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012 Nov 27; 126(22):2601-11. View Abstract
  35. Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ. 2012 Apr-Jun; 2(2):170-81. View Abstract
  36. Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2012 May 01; 302(9):L875-90. View Abstract
  37. Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension. Circulation. 2011 May 10; 123(18):1986-95. View Abstract
  38. Mesenchymal stromal cells expressing heme oxygenase-1 reverse pulmonary hypertension. Stem Cells. 2011 Jan; 29(1):99-107. View Abstract
  39. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med. 2009 Dec 01; 180(11):1122-30. View Abstract
  40. Divergent cardiopulmonary actions of heme oxygenase enzymatic products in chronic hypoxia. PLoS One. 2009 Jun 19; 4(6):e5978. View Abstract
  41. Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype. Am J Respir Cell Mol Biol. 2009 Mar; 40(3):305-13. View Abstract
  42. Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells. Circulation. 2008 Apr 22; 117(16):2114-22. View Abstract
  43. The role of heme oxygenase-1 in pulmonary disease. Am J Respir Cell Mol Biol. 2007 Feb; 36(2):158-65. View Abstract
  44. Hypoxia regulates bone morphogenetic protein signaling through C-terminal-binding protein 1. Circ Res. 2006 Aug 04; 99(3):240-7. View Abstract
  45. Exacerbation of hypoxia-induced pulmonary hypertension and vascular remodeling in COX-2 deficient mice. American Thoracic Society International Conference Proceedings. 2006; (3):A278. View Abstract
  46. Bone marrow derived mesenchymal stem cells expressing human heme oxygenase-1 (HO-1)reverse hypoxic pulmonary hypertension in HO-1 null mice. American Thoracic Society International Conference Proceedings. 2006; (3):A25. View Abstract
  47. Heme Oxygenase-1 (HO-1) overexpression prevents fibrosis and iron deposition in developmental lung injury. American Thoracic Society International Conference Proceedings. 2006; (3):A254. View Abstract
  48. Mechanisms of heme oxygenase-1-mediated cardiac and pulmonary vascular protection in chronic hypoxia: roles of carbon monoxide and bilirubin. Chest. 2005 Dec; 128(6 Suppl):578S-579S. View Abstract
  49. Extracellular acidosis induces heme oxygenase-1 expression in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol. 2005 Jun; 288(6):H2647-52. View Abstract
  50. HO-1 mediated cardiac protection in chronic hypoxia: Role of carbon monoxide and bilirubin. 2005. View Abstract
  51. Bone-marrow derived mesenchymal stem cells expressing human HO-1 reverse hypoxic pulmonary hypertension in HO-1 null mice . 2005. View Abstract
  52. Heme Oxygenase-1 overexpression decreases alveolar remodeling and iron deposition in developmental lung injury. 2005. View Abstract
  53. Hypoxia induces macrophage inflammatory protein-2 (MIP-2) gene expression in murine macrophages via NF-kappaB: the prominent role of p42/ p44 and PI3 kinase pathways. FASEB J. 2004 Jul; 18(10):1090-2. View Abstract
  54. Mechanisms of HO-1 cytopro-tection in hypoxic pulmonary hypertension. Pediatric Research. 2004; 55(4):A2638. View Abstract
  55. Effect of heme oxygenase-1 overexpression in two models of lung inflammation. Exp Biol Med (Maywood). 2003 May; 228(5):442-6. View Abstract
  56. Regulation of heme oxygenase-1 (HO-1) gene expression in vascular smooth muscle cells by extracellular acidosis. Pediatric Research. 2003; 53(4):A3220. View Abstract
  57. Regulation of Macro-phage Inflammatory Protein – 2 (MIP-2) gene expression by hypoxia. Am. J. Respir. Crit. Care Med. 2002; A546. View Abstract
  58. Targeted expression of heme oxygenase-1 and pulmonary responses to hypoxia. Heme Oxygenase in Biology and Medicine. 2002; 193-204. View Abstract
  59. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci U S A. 2001 Jul 17; 98(15):8798-803. View Abstract
  60. Hypoxia extends the life span of vascular smooth muscle cells through telomerase activation. Mol Cell Biol. 2001 May; 21(10):3336-42. View Abstract
  61. Herbimycin and geldanamycin inhibit the hypoxic induction of the vascular endothelial growth factor (VEGF) in pulmonary artery endothelial cells. Pediatric Research 2000. 2000; 47(4):A380. View Abstract
  62. Transgenic mice overexpressing Heme Oxygenase - 1 (HO-1) in the lung are protected from development of hypoxia-induced pulmonary hypertension: Evidence of anti inflammatory effects of HO-1. Pediatric Research. 2000; 47(4):A385. View Abstract
  63. Heme Oxygenase and pulmonary responses to hypoxia. Acta Hematologica. 2000; (103(1)):A276. View Abstract
  64. Extracellular acidosis induces Heme Oxygenase - 1 (HO-1) gene expression in vascular smooth muscle cells. Pediatric Research. 2000; 47(4):A386. View Abstract
  65. Hypoxic responses of vascular cells. Chest. 1998; 25S-28S. View Abstract
  66. Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells. J Biol Chem. 1997 Dec 26; 272(52):32804-9. View Abstract
  67. Ultraspiracle, a Drosophila retinoic X receptor alpha homologue, can mobilize the human thyroid hormone receptor to transactivate a human promoter. Biochemistry. 1997 Jul 29; 36(30):9221-31. View Abstract
  68. Retinoic acid alters the expression of pattern-related genes in the developing rat lung. Dev Dyn. 1996 Sep; 207(1):47-59. View Abstract
  69. Retinoic acid induces changes in the pattern of airway branching and alters epithelial cell differentiation in the developing lung in vitro. Am J Respir Cell Mol Biol. 1995 May; 12(5):464-76. View Abstract
  70. Structural characterization and specificity of expression of E2F-5: a new member of the E2F family of transcription factors. Cell Mol Biol Res. 1995; 41(3):147-54. View Abstract
  71. Regulation of renal rK1-kallikrein in spontaneously hypertensive rats. Ren Physiol Biochem. 1993 May-Jun; 16(3):125-30. View Abstract
  72. DNA binding and heteromerization of the Drosophila transcription factor chorion factor 1/ultraspiracle. Proc Natl Acad Sci U S A. 1992 Dec 01; 89(23):11503-7. View Abstract
  73. Transgenic regulation of moth chorion gene promoters in Drosophila: tissue, temporal, and quantitative control of four bidirectional promoters. J Mol Evol. 1989 Dec; 29(6):486-95. View Abstract
  74. Isolation and characterization of cDNA clones encoding human liver glutamate dehydrogenase: evidence for a small gene family. Proc Natl Acad Sci U S A. 1988 May; 85(10):3494-8. View Abstract
  75. A short 5'-flanking DNA region is sufficient for developmentally correct expression of moth chorion genes in Drosophila. Proc Natl Acad Sci U S A. 1987 Nov; 84(22):7987-91. View Abstract
  76. Developmental control and evolution in the chorion gene families of insects. Adv Genet. 1987; 24:223-42. View Abstract
  77. Evolution of Structural Genes and Regulatory Elements for the Insect Chorion. In: () 1987; Vol. 8, pp. Development as an Evolutionary Process, R. Raff and E.C. Raff, eds. 1987; 161-178. View Abstract
  78. Developmental control and evolution in the chorion gene families of insects. Advances in Genetics, J.G. Scandalios, ed. 1987; 223-242. View Abstract
  79. Regulatory elements controlling chorion gene expression are conserved between flies and moths. Nature. 1985 Oct 3-9; 317(6036):453-6. View Abstract
  80. Studies on the developmentally regulated expression and amplification of insect chorion genes. Cold Spring Harb Symp Quant Biol. 1985; 50:537-47. View Abstract
  81. An upstream regulatory domain of avian tumor virus long terminal repeat is required for the expression of a procaryotic neomycin gene in eucaryotic cells. Mol Cell Biol. 1983 Nov; 3(11):1975-84. View Abstract
  82. Studies on the structure and organization of avian sarcoma proviruses in the rat XC cell line. J Gen Virol. 1983 Sep; 64 (Pt 9):1885-93. View Abstract
  83. Localization of active promoters for eucaryotic RNA polymerase II in the long terminal repeat of avian sarcoma virus DNA. Mol Cell Biol. 1983 May; 3(5):811-8. View Abstract
  84. Studies on the methylation of avian sarcoma proviruses in permissive and non-permissive cells. J Gen Virol. 1983 Feb; 64 (Pt 2):429-35. View Abstract
  85. Studies on transcriptional control elements within the retroviral long terminal repeat. 1983. View Abstract
  86. Restriction endonuclease and nucleotide sequence analyses of molecularly cloned unintegrated avian tumor virus DNA: structure of large terminal repeats in circle junctions. J Virol. 1982 Apr; 42(1):346-51. View Abstract
  87. An avian tumor virus promoter directs expression of plasmid genes in Escherichia coli. Gene. 1981 Dec; 16(1-3):217-25. View Abstract
  88. Cloning of avian tumor virus DNA fragments in plasmid pBR322: evidence for efficient transcription in E. coli from a virus-coded promoter. Gene. 1980 Dec; 12(1-2):113-21. View Abstract
  89. Binding of Escherichia coli RNA polymerase to a specific site located near the 3'-end of the avaian sarcoma virus genome. Biochim Biophys Acta. 1980 May 30; 607(3):457-69. View Abstract
  90. Modification of avian sarcoma proviral DNA sequences in nonpermissive XC cells but not in permissive chicken cells. J Virol. 1980 May; 34(2):569-72. View Abstract

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