walters1 Matthew Walters, PhD
Assistant Professor of Medicine
Division of Pulmonary, Critical Care and Sleep Medicine
Department of Medicine
University of Oklahoma Health Sciences Center

800 N. Research Parkway
Building 800, 4th Floor, Rm 410
Oklahoma City, OK 73104
Office: 405-271-3803 (on campus 13803)
Lab: 405-271-8000 ext 57387 or 57357 (on campus 57387 or 57357)
Matthew-S-Walters@ouhsc.edu

Education

  • Ph.D., Molecular Virology, School of Medicine, University of Leeds, Leeds, UK
  • BSc (1st Class Honors) Genetics, University of Liverpool, Liverpool, UK

Pre-OUHSC

  • Assistant Research Professor, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA
  • Associate Research Scientist, Department of Microbiology and Immunology, Columbia University, New York, NY, USA
  • Postdoctoral Research Scientist, Department of Microbiology and Immunology, Columbia University, New York, NY, USA

Memberships

  • American Thoracic Society (ATS)

Research Summary
The major focus of my laboratory is to understand the processes that regulate lung regeneration during health and in response to environmental insult, including cigarette smoke. Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the US, with an estimated 90% of cases caused by cigarette smoking. Currently there is no cure for COPD and therapeutic options to treat the disease are limited. The earliest cigarette smoking-induced changes relevant to the pathogenesis of COPD occur in the airway epithelium, a multi-cellular tissue that covers the luminal surface of the conducting airways of the lung. The airway epithelium functions as a barrier to protect the lung from pathogens and harmful environmental factors via the action of specialized cells including basal, secretory and ciliated cells. Basal cells (BC) are the stem/progenitor population of the human airway epithelium that differentiate into secretory and ciliated cells during normal epithelial turnover and in response to injury. This process is highly coordinated and is regulated by multiple signaling pathways and cellular interactions between BC and other cell types in the lung microenvironment. Cigarette smoking alters the normal differentiation response of BC, resulting in epithelial remodeling which negatively impacts the overall function of the airway epithelium and health of the lung. Our goal is to identify key pathways and define critical cell interactions that regulate the stem/progenitor phenotype of BC within the lung microenvironment during health and disease. To achieve this goal, our lab uses different molecular and cellular approaches, including in vitro differentiation models to mimic the in vivo airway epithelium and targeting of specific genes/pathways via lentivirus-mediated gene transfer/knockdown and CRISPR-directed genome editing. Combined, these approaches will help identify pathways and cellular interactions that regulate differentiation of BC providing novel targets for developing new therapeutic and/or regenerative medicine approaches for the treatment of smoking-induced lung disease, including COPD.

Current Projects
Notch signaling is an evolutionary conserved developmental pathway that has a major role in regulating airway epithelial structure and has been implicated in the development of airway epithelial remodeling associated with smoking and COPD. Activation of canonical Notch signaling operates in a cell–cell contact-dependent manner involving binding of one of five plasma membrane-bound ligands (DLL1, DLL3, walters2DLL4, JAG1 and JAG2) to one of four receptors (NOTCH1-4) on the plasma membrane of a neighboring cell (Fig 1). Upon ligand binding, the receptor is cleaved by the γ-secretase enzyme at the intracellular transmembrane region, resulting in release of the Notch intracellular domain (NICD) into the cytoplasm. The NICD translocates to the nucleus and forms an active transcriptional complex with the DNA binding protein RBPJK and additional co-activators. The resulting complex binds within the promoters of multiple target genes (downstream effectors) to regulate their expression, including transcription factors (e.g. HES and HEY family genes) that mediate Notch downstream responses (Fig 1). Prior studies from our lab have demonstrated that constitutive activation of Notch signaling in human basal stem/progenitor cells (BC) via the NOTCH1 and 3 receptors in vitro promotes secretory cell differentiation with a corresponding decrease in ciliated cell differentiation characteristic of goblet cell hyperplasia/metaplasia, an epithelial remodeling feature associated with smoking and COPD. However, the downstream effectors/responses that regulate Notch-mediated secretory cell differentiation are poorly understood or unknown. Therefore, current projects in the lab are focused on characterizing the genome-wide transcriptional responses following Notch signaling activation in human BC and testing the ability of candidate Notch downstream effectors to regulate secretory cell differentiation. In turn, these effectors may serve as candidate targets for new therapies to target the Notch pathway to suppress goblet cell hyperplasia/metaplasia and treat individuals with COPD.

Current Laboratory Personnel

Dr. Manish Bodas, Postdoctoral Research Fellow

Andrew Ryan Moore, Research Assistant

Current Openings
Please inquire regarding current research opportunities in the lab.

Selected Publications (in reverse chronological order)
Taken from 36 peer-reviewed articles.* Indicates co-first author

  • Zhang H, Yang J, Walters MS, Staudt MR, Strulovici-Barel Y, Salit J, Mezey JG, Leopold PL, and Crystal RG. Mandatory role of HMGA1 in human airway epithelial normal differentiation and post-injury regeneration. Oncotarget. 2018 Feb 16;9(18):14324-14337. doi: 10.18632/oncotarget.24511. eCollection 2018 Mar 6. PubMed PMID: 29581847. PubMed Central PMCID: PMC5865673.
  • Wang G, Zhou H, Strulovici-Barel Y, Al-Hijji M, Ou X, Salit J, Walters MS, Staudt MR, Kaner RJ, and Crystal RG. Role of OSGIN1 in mediating smoking-induced autophagy in the human airway epithelium. Autophagy. 2017 Jul 3;13(7):1205-1220. doi: 10.1080/15548627.2017.1301327. [Epub 2017 May 26]. PubMed PMID: 28548877. PubMed Central PMCID: PMC5529077.
  • Walters MS*, Salit J*, Ju JH, Staudt MR, Kaner RJ, Rogalski AM, Sodeinde TB, Rahim R, Strulovici-Barel Y, Mezey JG, Almulla AM, Sattar H, Mahmoud M, and Crystal RG. Waterpipe smoking induces epigenetic changes in the small airway epithelium. PLoS One. 2017 Mar 8;12(3):e0171112. doi: 10.1371/journal.pone. 0171112. PubMed PMID: 28273093. PubMed Central PMCID: PMC5342191.
  • Gomi K, Tang Y, Arbelaez V, Crystal RG, Walters MS. Endothelial Cell Mediated Promotion of Ciliated Cell Differentiation of Human Airway Basal Cells via Insulin and Insulin-Like Growth Factor 1 Receptor Mediated Signaling. Stem Cell Rev. 2017 Apr;13(2):309-317. doi: 10.1007/s12015-016-9707-z. [Epub ahead of print] PubMed PMID: 28050756.
  • Strulovici-Barel Y, Shaykhiev R, Salit J, Deeb RS, Krause A, Kaner RJ, Vincent TL, Agosto-Perez F, Wang G, Hollmann C, Shanmugam V, Almulla AM, Sattar H, Mahmoud M, Mezey JG, Gross SS, Staudt MR, Walters MS, Crystal RG. Pulmonary Abnormalities in Young, Light-Use Waterpipe (Hookah) Smokers. Am J Respir Crit Care Med. 2016 Sep 1;194(5):587-95. doi: 10.1164/rccm.201512-2470OC. PubMed PMID: 27007171; PubMed Central PMCID: PMC5027211.
  • Gomi K, Staudt MR, Salit J, Kaner RJ, Heldrich J, Rogalski AM, Arbelaez V, Crystal RG, Walters MS. JAG1-Mediated Notch Signaling Regulates Secretory Cell Differentiation of the Human Airway Epithelium. Stem Cell Rev. 2016 Aug;12(4):454-63. doi: 10.1007/s12015-016-9656-6. PubMed PMID: 27216293; PubMed Central PMCID: PMC4926772.
  • Zhou H, Brekman A, Zuo WL, Ou X, Shaykhiev R, Agosto-Perez FJ, Wang R, Walters MS, Salit J, Strulovici-Barel Y, Staudt MR, Kaner RJ, Mezey JG, Crystal RG, Wang G. POU2AF1 Functions in the Human Airway Epithelium To Regulate Expression of Host Defense Genes. J Immunol. 2016 Apr 1;196(7):3159-67. doi: 10.4049/jimmunol.1502400. PubMed PMID: 26927796; PubMed Central PMCID: PMC4799774.
  • Deeb RS*, Walters MS*, Strulovici-Barel Y, Chen Q, Gross SS, Crystal RG. Smoking-Associated Disordering of the Airway Basal Stem/Progenitor Cell Metabotype. Am J Respir Cell Mol Biol. 2016 Feb;54(2):231-40. doi: 10.1165/rcmb.2015-0055OC. PubMed PMID: 26161876; PubMed Central PMCID: PMC4821042.
  • Ding BS, Gomi K, Rafii S, Crystal RG, Walters MS. Endothelial MMP14 is required for endothelial-dependent growth support of human airway basal cells. J Cell Sci. 2015 Aug 15;128(16):2983-8. doi: 10.1242/jcs.168179. PubMed PMID: 26116571; PubMed Central PMCID: PMC4541042.
  • Gomi K, Arbelaez V, Crystal RG, Walters MS. Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway. PLoS One. 2015 Feb 20;10(2):e0116507. doi: 10.1371/journal.pone.0116507. PubMed PMID: 25700162; PubMed Central PMCID: PMC4336283.
  • Tilley AE, Walters MS, Shaykhiev R, Crystal RG. Cilia dysfunction in lung disease. Annu Rev Physiol. 2015;77:379-406. doi: 10.1146/annurev-physiol-021014-071931. Review. PubMed PMID: 25386990; PubMed Central PMCID: PMC4465242.
  • Durgan J, Tao G, Walters MS, Florey O, Schmidt A, Arbelaez V, Rosen N, Crystal RG, Hall A. SOS1 and Ras regulate epithelial tight junction formation in the human airway through EMP1. EMBO Rep. 2015 Jan;16(1):87-96. doi: 10.15252/embr.201439218. PubMed PMID: 25394671; PubMed Central PMCID: PMC4304732.
  • Brekman A, Walters MS, Tilley AE, Crystal RG. FOXJ1 prevents cilia growth inhibition by cigarette smoke in human airway epithelium in vitro. Am J Respir Cell Mol Biol. 2014 Nov;51(5):688-700. doi: 10.1165/rcmb.2013-0363OC. PubMed PMID: 24828273; PubMed Central PMCID: PMC4224080.
  • Staudt MR, Buro-Auriemma LJ, Walters MS, Salit J, Vincent T, Shaykhiev R, Mezey JG, Tilley AE, Kaner RJ, Ho MW, Crystal RG. Airway Basal stem/progenitor cells have diminished capacity to regenerate airway epithelium in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014 Oct 15;190(8):955-8. doi: 10.1164/rccm.201406-1167LE. PubMed PMID: 25317467; PubMed Central PMCID: PMC4299582.
  • Walters MS*, De BP*, Salit J, Buro-Auriemma LJ, Wilson T, Rogalski AM, Lief L, Hackett NR, Staudt MR, Tilley AE, Harvey BG, Kaner RJ, Mezey JG, Ashbridge B, Moore MA, Crystal RG. Smoking accelerates aging of the small airway epithelium. Respir Res. 2014 Sep 24;15:94. doi: 10.1186/s12931-014-0094-1. PubMed PMID: 25248511; PubMed Central PMCID: PMC4189169.
  • Ryan DM, Vincent TL, Salit J, Walters MS, Agosto-Perez F, Shaykhiev R, Strulovici-Barel Y, Downey RJ, Buro-Auriemma LJ, Staudt MR, Hackett NR, Mezey JG, Crystal RG. Smoking dysregulates the human airway basal cell transcriptome at COPD risk locus 19q13.2. PLoS One. 2014 Feb 3;9(2):e88051. doi: 10.1371/journal.pone.0088051. PubMed PMID: 24498427; PubMed Central PMCID: PMC3912203.
  • Walters MS, Gomi K, Ashbridge B, Moore MA, Arbelaez V, Heldrich J, Ding BS, Rafii S, Staudt MR, Crystal RG. Generation of a human airway epithelium derived basal cell line with multipotent differentiation capacity. Respir Res. 2013 Dec 3;14:135. doi: 10.1186/1465-9921-14-135. PubMed PMID: 24298994; PubMed Central PMCID: PMC3907041.
  • Buro-Auriemma LJ, Salit J, Hackett NR, Walters MS, Strulovici-Barel Y, Staudt MR, Fuller J, Mahmoud M, Stevenson CS, Hilton H, Ho MW, Crystal RG. Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression. Hum Mol Genet. 2013 Dec 1;22(23):4726-38. doi: 10.1093/hmg/ddt326. PubMed PMID: 23842454; PubMed Central PMCID: PMC3888123.
  • Didon L, Zwick RK, Chao IW, Walters MS, Wang R, Hackett NR, Crystal RG. RFX3 modulation of FOXJ1 regulation of cilia genes in the human airway epithelium. Respir Res. 2013 Jul 3;14:70. doi: 10.1186/1465-9921-14-70. PubMed PMID: 23822649; PubMed Central PMCID: PMC3710277.
  • Curradi G*, Walters MS*, Ding BS*, Rafii S, Hackett NR, Crystal RG. Airway basal cell vascular endothelial growth factor-mediated cross-talk regulates endothelial cell-dependent growth support of human airway basal cells. Cell Mol Life Sci. 2012 Jul;69(13):2217-31. doi: 10.1007/s00018-012-0922-8. PubMed PMID: 22382924; PubMed Central PMCID: PMC3633460.
  • Hackett NR*, Shaykhiev R*, Walters MS*, Wang R, Zwick RK, Ferris B, Witover B, Salit J, Crystal RG. The human airway epithelial basal cell transcriptome. PLoS One. 2011 May 4;6(5):e18378. doi: 10.1371/journal.pone.0018378. PubMed PMID: 21572528; PubMed Central PMCID: PMC3087716.

Complete List of Published Work in MyBibliography:

https://www.ncbi.nlm.nih.gov/myncbi/browse/collection/48354519/?sort=date&direction=+descending