Kelly McNagny

Contact InformationKelly McNagny
2222 Health Sciences Mall
Vancouver, BC, Canada V6T 1Z3
Tel 1-604-822-7824
kelly@brc.ubc.ca

Current Positions

  • Professor, Medical Genetics, Medicine
  • Biomedical Research Centre

Research Interests

My laboratory is interested in two aspects of hematopoietic stem cell biology: 1) the transcriptional and signaling network that regulates the commitment of multipotent progenitors to a specific lineage, and 2) the surface receptors expressed by HSC that regulate their interacts with their microenvironment.

Transcriptional and signaling networks
We are focusing on the regulatory mechanisms that govern mast cell and eosinophil production. These are relatively rare cells that are responsible for most of the pathology in chronic allergy and asthma and therefore may represent good targets for clinical intervention. We are using a number of transgenic mouse models to identify the factors that govern mast cell and eosinophil formation, homing and function and to perturb these processes during normal development.

Surface molecules expressed by HSC
We have focused predominantly on CD34-type proteins. CD34 is a cell surface sialomucin and the most widely used marker of hematopoietic stem cells and vascular endothelia. Recently we identified two novel receptors, Podocalyxin (also called MEP21, gp135, Thrombomucin and PCLP1) and Endoglycan that are also expressed by hematopoietic stem/progenitor cells and vasculature. We have shown that, together with CD34, these additional molecules comprise a gene family and that all three are probably derived from a common ancestral gene. Surprisingly, despite the extensive use of CD34 as a stem cell marker, virtually nothing is known of its function and it has alternatively be touted as a: 1) blocker of HSC differentiation 2) enhancer of HSC proliferation 3) bone marrow homing receptor 4) pro-adhesive receptor 5) anti-adhesive receptor.

Targeted deletion of the CD34 gene in mice has only fueled the debate concerning its function since these mice exhibit extremely subtle perturbations in normal hematopoietic function that could be used to support each of the above hypotheses. The discovery of two novel members of this gene family with overlapping expression patterns, has allowed us to: (1) re-evaluate these results in light of the potential for functional compensation and, (2) to generate compound mutant mice to test the true function of these receptors. In aggregate, these studies have allowed us to prove that the CD34 family of proteins function predominantly as anti-adhesion molecules, or “molecular Teflon”. Thus, they enhance the mobility and invasiveness of hematopoietic cells and on non-hematopoietic cells, they are able to disrupt cell-cell junctional complexes between neighboring adherent cells (vascular endothelia or podocytes in the kidney, for example). This is not a constitutive function, but is tightly regulated by a set of proteins that bind to the cytoplasmic tail of CD34-type proteins and regulate their sub-cellular localization and proximity to adhesion molecules. Preliminary data suggest that loss of CD34-type proteins leads to defects in hematopoietic function by preventing the HSC from entering the appropriate micro-environments (due to excessive adhesion). Similarly, we have shown that loss of these proteins can lead to dysregulation of blood pressure, presumably due to increased cell-cell adhesion and decreased vascular permeability. Finally, we have shown that these same “anti-adhesion” molecules are upregulated in an aggressive subset of epithelial tumors and lead to increased invasiveness and loss of cell polarity. They may, thus, prove to be excellent prognostic indicators of poor outcome tumors and provide a means of identifying these cancers early for aggressive therapy.

Selected Publications

  1. Saadala A, Osman MA, Gurish MF, Dennis KL, Blatner NR, Pezeshki A, McNagny KM, Cheroutre H, Gounari H, Khazaie K. Mast cells promote small bowel cancer in a tumor stage-specific and cytokine dependent manner. Proc. Nat. Acad. Science (in press, 2018)
  2. Kim YK*, Refaeli I*, Brooks CR, Gulieva RE, Hughes MR, Cruz NM, Fu, H, Pippin J, Shankland SJ, Vogl, AW, McNagny KM#, Freedman BS#. Gene editing in kidney organoids derived from pluripotent stem cells establishes a functional model of human podocyte development. Stem Cells 35: 2366-2378, 2017. #Co-Corresponding author.
  3. Cait A, Hughes MR, Antignano F, Cait J, Dimitriu PA, Maas KR, Reynolds LA, Hacker L, Mohr J, Finlay BB, Zaph C, McNagny KM, Mohn WW. Microbiome-driven allergic lung inflammation is ameliorated by short chain fatty acids. Mucosal Immunology. (in press, 2017).
  4. Kang HG, Lee M, Lee KB, Hughes M, Kwon BS, Lee S, McNagny KM, Ahn YH, Ko JM, Ha IS, Choi M, Cheong Loss of podocalyxin causes a novel syndromic type of congential nephrotic syndrome.  Exp. & Mol. Med. 49: e414, 2017.
  5. Lo BC, Gold MJ, Scheer S, Hughes MR, Cait J, Debruin E, Chu FSF, Walker DC, Soliman H, Rossi FM, Blanchet MR, Perona-Wright G, Zaph C, and McNagny, KM. Loss of vascular CD34 results in increased sensitivity to lung injury. Am J Resp Cell Mol Bio. 57: 651-661,
  6. de Bock CE, Hughes MR, Snyder K, Winterhalter C, Alley S, Sadeqzadeh E, Dun MD, Hall RA, McNagny KM, Elati M, Molloy TJ, Hondermarck H, Thorne RF. Protein interaction screening identifies SH3RF1 as a new regulator of FAT1 protein levels in breast cancer. FEBs Letters. 591: 667-678, 2017.
  7. Bernatchez, E, Gold MJ, Langlois A, Blais-Lecours P, Duchaine C, Marsolais D, McNagny, KM, Blanchet M-R. Methanosphaera stadtmanae induces a type IV hypersensitivity response in a mouse model of airway inflammation. Rep. 5: e13163, 2017.x

Education

  • Postdoctorate (Molecular Biology) European Molecular Biology Lab, Germany, 1996
  • Ph.D. (Immunology) University of Alabama at Birmingham, USA, 1990
  • B. Sc. (Biology and Biotechnology Fermentation Biology), Worcester Polytechnic Institute, USA, 1984