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Cystic fibrosis (CF) is the most common lethal monogenetic disease in the Caucasian population. It is a heterogeneous disease with over 1,500 identified genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). As a result, patients exhibit a wide range of clinical manifestations.
There is no cure or effective therapy for over 90% of CF patients. Recent discoveries as well as FDA approval of medications that help to correct the underlying defect in CF are promising. Looking forward, a personalized medicine approach will be essential to the identification of the best therapeutics for each individual patient.
A readily available and renewable supply of human CF airway cells is vital to future drug discovery efforts. Stem cells have the ability to self-renew and generate a variety of daughter cells with specialized functions.
In theory, these characteristics allow airway stem cells to be utilized as a replacement therapy for cells that carry genetic mutations (such as CF) or have been damaged due to injury or disease. These traits also allow stem cells to serve as a source of specialized airway cells that are the gold standard for the study of CF physiology and drug screening.
The laboratory of Hongmei Mou, PhD, aims to generate in vitro human model systems representative of lung diseases. These models, named airway and lung in a dish, are derived from patient and disease-specific airway and lung tissues, or from induced pluripotent stem cells (iPSC), and will possess characteristic physiological functions.
Our lab has developed a novel method to convert normal and diseased iPSCs into lung epithelial stem cells that can both self-renew and give rise to multiple differentiated airway and alveolar cells. In addition, we have established a reproducible culture system in which primary airway and lung stem cells can be expanded without suffering loss of stemness or differentiation potential.
We employ a two-pronged approach to study pulmonary disease biology, physiology and pathogenesis to accelerate the development of cell replacement therapies for endogenous epithelial cells that harbor disease-causing mutations, such as in BPD, cystic fibrosis or injured lungs.
Hongmei Mou, PhD Principal Investigator, Mucosal Immunology & Biology Research Center Assistant Professor in Pediatrics, Harvard Medical School
Michael Wood Research Technician
Currently one major technical bottleneck in developing personalized therapies for airway diseases such as cystic fibrosis (CF) is the inability to procure a large number of functional airway epithelial cells. Since stem cells have the ability to self-renew and to give rise to multiple types of differentiated cells, they can contribute to developing personalized therapies.
In principle two unlimited populations of airway stem cells can be generated in a patient-specific manner. The first cell population consists of adult airway stem cells in which endogenous stem cells are isolated and expanded indefinitely. The second cell population is derived from patient-specific induced pluripotent stem cells (iPSCs) that efficiently differentiate induced cells into adult-like airway stem or progenitor cells.
Dr. Mou’s laboratory is focused on the generation of unlimited cells, from primary airway stem cells or iPSCs, with an ensured differentiation capacity. These cells are a resource for disease modeling, drug screening (personalized medicine), and repopulating damaged tissues (cell therapy).
Neonatal lung defects are a major cause of early mortality and long-term disability in infants. A better understanding of the cellular and molecular basis of normal human pulmonary development will help define the mechanisms that cause abnormal development of the embryonic lung resulting in a birth defect.
Specifically, our lab is interested in the study of the cellular and molecular mechanisms underlying human fetal airway and lung progenitor cell specification, determination, plasticity and related pathogenesis, such as congenital and neonatal abnormalities in the lung.
Bryan P. Hurley, PhD, Assistant Professor of Pediatrics, Harvard Medical School
Martin Mense , PhD, Vice President, Drug Discovery, Cystic Fibrosis Foundation Therapeutics
Steven Rowe, MD, MSPH, Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Medical Research and Director, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham
Paul Lerou, MD, Chief, Neonatology and Newborn Medicine, MassGeneral Hospital for Children
Jayaraj Rajagopal, MD, Principal Investigator, Center for Regenerative Medicine and Physician, Pulmonary and Critical Care Unit
Lynch TJ, Anderson PJ, Rotti PG, Tyler SR, Crooke AK, Choi SH, Montoro DT, Silverman CL, Shahin W, Zhao R, Jensen-Cody CW, Adamcakova-Dodd A, Evans TIA, Xie W, Zhang Y, Mou H, Herring BP, Thorne PS, Rajagopal J, Yeaman C, Parekh KR, Engelhardt JF. Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium. Cell Stem Cell. 2018 May 03; 22(5):779. PMID: 29727685.
Tata PR, Chow RD, Saladi SV, Tata A, Konkimalla A, Bara A, Montoro D, Hariri LP, Shih AR, Mino-Kenudson M, Mou H, Kimura S, Ellisen LW, Rajagopal J. Developmental History Provides a Roadmap for the Emergence of Tumor Plasticity. Dev Cell. 2018 03 26; 44(6):679-693.e5. PMID: 29587142.
Mou H. Quality before Quantity: Inspecting CFTR. Dev Cell. 2018 03 26; 44(6):655-656. PMID: 29587139.
Yonker LM, Pazos MA, Lanter BB, Mou H, Chu KK, Eaton AD, Bonventre JV, Tearney GJ, Rajagopal J, Hurley BP. Neutrophil-Derived Cytosolic PLA2α Contributes to Bacterial-Induced Neutrophil Transepithelial Migration. J Immunol. 2017 Sep 8. PMID: 28887431.
Yonker LM, Mou H, Chu KK, Pazos MA, Leung H, Cui D, Ryu J, Hibbler RM, Eaton AD, Ford TN, Falck JR, Kinane TB, Tearney GJ, Rajagopal J, Hurley BP. Development of a Primary Human Co-Culture Model of Inflamed Airway Mucosa. Sci Rep. 2017 Aug 15; 7(1):8182. PMID: 28811631.
Saladi SV, Ross K, Karaayvaz M, Tata PR, Mou H, Rajagopal J, Ramaswamy S, Ellisen LW. ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation, and Poor Prognosis. Cancer Cell. 2017 Jan 09; 31(1):35-49. PMID: 28041841.
Mou H, Vinarsky V, Tata PR, Brazauskas K, Choi SH, Crooke AK, Zhang B, Solomon GM, Turner B, Bihler H, Harrington J, Lapey A, Channick C, Keyes C, Freund A, Artandi S, Mense M, Rowe S, Engelhardt JF, Hsu YC, Rajagopal J. Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells. Cell Stem Cell. 2016 Aug 04; 19(2):217-231. PMID: 27320041; PMCID: PMC4975684
Mou H, Brazauskas K, Rajagopal J. Personalized medicine for cystic fibrosis: establishing human model systems. Pediatr Pulmonol. 2015 Oct; 50 Suppl 40:S14-23. PMID: 26335952.
Dowdall JR, Sadow PM, Hartnick C, Vinarsky V, Mou H, Zhao R, Song PC, Franco RA, Rajagopal J. Identification of distinct layers within the stratified squamous epithelium of the adult human true vocal fold. Laryngoscope. 2015 Sep; 125(9):E313-9. PMID: 25988619; PMCID: PMC4910522.
Pardo-Saganta A, Law BM, Tata PR, Villoria J, Saez B, Mou H, Zhao R, Rajagopal J. Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations. Cell Stem Cell. 2015 Feb 05; 16(2):184-97. PMID: 25658372; PMCID: PMC4334442.
Gilpin SE, Ren X, Okamoto T, Guyette JP, Mou H, Rajagopal J, Mathisen DJ, Vacanti JP, Ott HC. Enhanced lung epithelial specification of human induced pluripotent stem cells on decellularized lung matrix. Ann Thorac Surg. 2014 Nov; 98(5):1721-9; discussion 1729. PMID: 25149047; PMCID: PMC4252658.
Zhao R, Fallon TR, Saladi SV, Pardo-Saganta A, Villoria J, Mou H, Vinarsky V, Gonzalez-Celeiro M, Nunna N, Hariri LP, Camargo F, Ellisen LW, Rajagopal J. Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. Dev Cell. 2014 Jul 28; 30(2):151-65. PMID: 25043474; PMCID: PMC4130488.
Tata PR, Mou H, Pardo-Saganta A, Zhao R, Prabhu M, Law BM, Vinarsky V, Cho JL, Breton S, Sahay A, Medoff BD, Rajagopal J. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature. 2013 Nov 14; 503(7475):218-23. PMID: 24196716; PMCID: PMC4035230.
Mou H, Zhao R, Sherwood R, Ahfeldt T, Lapey A, Wain J, Sicilian L, Izvolsky K, Musunuru K, Cowan C, Rajagopal J. Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs. Cell Stem Cell. 2012 Apr 06; 10(4):385-97. PMID: 22482504; PMCID: PMC3474327.
Longmire TA, Ikonomou L, Hawkins F, Christodoulou C, Cao Y, Jean JC, Kwok LW, Mou H, Rajagopal J, Shen SS, Dowton AA, Serra M, Weiss DJ, Green MD, Snoeck HW, Ramirez MI, Kotton DN. Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell. 2012 Apr 06; 10(4):398-411. PMID: 22482505; PMCID: PMC3322392.
Paglia MJ, Mou H, Cote RH. Regulation of photoreceptor phosphodiesterase (PDE6) by phosphorylation of its inhibitory gamma subunit re-evaluated. J Biol Chem. 2002 Feb 15; 277(7):5017-23. PMID: 11741972.
Mou H, Cote RH. The catalytic and GAF domains of the rod cGMP phosphodiesterase (PDE6) heterodimer are regulated by distinct regions of its inhibitory gamma subunit. J Biol Chem. 2001 Jul 20; 276(29):27527-34. PMID: 11375400.
Mou H, Grazio HJ, Cook TA, Beavo JA, Cote RH. cGMP binding to noncatalytic sites on mammalian rod photoreceptor phosphodiesterase is regulated by binding of its gamma and delta subunits. J Biol Chem. 1999 Jun 25; 274(26):18813-20. PMID: 10373499.
Hongmei Mou, PhD
Mucosal Immunology & Biology Research Center
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