Christopher McCulloch

Christopher McCulloch is a full professor in the Faculty of Dentistry, University of Toronto.  

His primary appointment is Director of the Matrix Dynamics Group. The group currently consists of five principal investigators and focuses on the regulation of connective tissue matrix proteins in health and disease.

Dr McCulloch received a Career Scientist Award from the Ontario Ministry of Health (1984-1994), a Scientist Award from Columbia University (New York City), a Distinguished Alumnus Award from the Faculty of Dentistry, University of Toronto (2011), the Distinguished Scientist Award for Research in Oral Biology from the International Association of Dental Research (IADR) in 2009 and a Canada Research Chair (Tier 1) in Matrix Dynamics (2006-2020).  

He has been a consultant for the Royal College of Dental Surgeons of Ontario (RCDSO) since 2006.

His research focuses on the remodelling of connective tissue matrices.

He initially established the location and proliferative behaviour of cells in the periodontal ligament and showed that subpopulations of these cells can undergo self-renewal, a characteristic of stem cells. He used actin isoform analyses to establish that alpha-smooth muscle actin is a differentiation marker for contractile fibroblasts from the periodontium and is required for collagen contraction.

Further, he has shown that the actin binding protein filamin A is required for protection of cells in mechanically active environments.

Finally, Chris has defined the role of collagen phagocytosis in connective tissue matrix remodeling and established the importance of this pathway for the formation of fibrotic lesions.

Research Synopsis

From 1998 – present: demonstrated that mechanical forces regulate the differentiation of myofibroblasts

The differentiation of fibroblasts into myofibroblasts is critical for fibrosis which is characterized by enhanced production of collagen and by a large increase of contractile activity.

The increased tensile forces generated by myofibroblasts are attributable to the expression of alpha smooth muscle actin, the defining phenotypic marker of myofibroblast.These are particularly important cells in the formation of fibrotic lesions of connective tissues.

Impact

Developed substrates and culture systems that enabled definition of how fibroblasts differentiate into myofibroblasts.

Papers: (Arora et al. Am. J. Path. 1999; Arora and McCulloch Am. J. Path. 1999; Wang et al. J. Biol. Chem. 2002; Wang et al. Am. J. Physiol. 2003; ibid. J. Biol. Chem. 2005; Zhang et al. J. Cell Science 2007; Pho et al. Am. J. Physiol. 2008; Chan et al. J. Cell Science 2009).

From 1995 – present: showed that actin filaments regulate inflammatory cytokine signaling

Found that actin filaments in focal adhesions are required for IL-1 signaling in fibroblasts. The experimental work links the actin cytoskeleton to the calcium signaling system in fibroblasts, which may impact on a wider variety of inflammatory signals than previously thought.

Impact

This discovery led to the discovery of new targets to reduce chronic inflammation and the filing of a patent application.

Papers: (Arora et al. J. Biol. Chem.  1995; MacGillivray et al. J. Biol. Chem. 2000; MacGillivray et al. J. Biol. Chem. 2003; Wang et al. FASEB. Journal 2003; Wang et al. J. Biol. Chem 2005; Wang et al. J. Biol. Chem. 2006; McCulloch et al. Nature Reviews Drug Discovery 2007; Wang et al. J. Biol. Chem. 2009; Wang et al. J. Biol. Chem. 2010; Wang et al. FASEB J. 2011; Rajshankar et al. FASEB J. 2012; Wang et al. Biochem J. 2013).

From 1998 – present: demonstrated a critical role for the fibroblast in collagen degradation by phagocytosis

Over a 15+ year time period showed that collagen phagocytosis is a crucial mechanism for remodelling of the extracellular matrix and demonstrated for the first time that perturbations in collagen recognition and calcium signaling to actin were responsible for the formation of fibrotic lesions in human periodontium.

Impact

The published work (1993-2013) and a large series of international and national presentations has provided the biological basis by which inflammatory cytokines and aging processes cause dysfunctional collagen homeostasis, leading to the formation of collagen overgrowth and fibrosis.

Papers: (Knowles et al. J. Cell Science 1991; Arora et al. J. Biol. Chem. 2000; Arora et al. J. Biol. Chem. 2001; Arora et al. Mol. Biol. Cell 2004; Mol Biol. Cell 2005; Lee et al. Mol Biol. Cell 2006; Arora et al. Mol Biol. Cell 2008; Arora et al. Mol. Biol. Cell 2009; Arora et al. J. Biol. Chem.2011; Arora et al. Mol. Biol. Cell 2013).

1998 – present: demonstrated that the actin cross linking protein filamin A protects cells against force-induced death

Cells in mechanically challenged environments elaborate protective systems to prevent cell death. Identified an actin binding protein (filamin A) that protects cells against mechanical loading by virtue of its ability to cross-link actin filaments and increase the rigidity of the cell membrane.

Introduced the idea of mechanoprotection and demonstrated a role for filamin A in protecting cells against stretch-induced apoptosis. (Glogauer et al. J. Biol. Chem. 1998; Kainulainen et al. J. Biol. Chem. 2001).

Impact

Showed that mechanoprotective signals regulate the promoter of the filamin A gene through the activation of Sp1 binding, a process mediated by the MAP kinase p38 (D’Addario et al. J. Biol. Chem. 2001; D’Addario et al. J. Biol. Chem. 2002) and is modified by microtubules (D’Addario et al. J. Biol. Chem. 2003; Mol Biol. Cell 2005).

Showed that mechanical signalling through filamin A requires Fil Gap (Schifrin et al. 2009), involves the protein unfolding pathway (Mak et al.  J. Biol Chem. 2008) and signals through PAK and Rac (Shifrin et al. Biochem. J. 2012).

The McCulloch Lab

Dr McCulloch has defined critical signaling systems that regulate the structure and function of extracellular matrices in periodontal and cardiac connective tissues.

The ultimate goal of his research is to define new therapies for periodontal and cardiovascular disorders.

Since 2006, Dr McCulloch has:

• trained >50 undergraduate and graduate students
• generated over 70 peer-reviewed publications
• two patent applications
• won several major scientific awards

Consistent with the University of Toronto’s Strategic Research Plan, Dr McCulloch has played a central role in developing major collaborative research and training programs that cross disciplinary and institutional boundaries.

Selected Publications

Matthews DC, McNeil K, Brillant M, Tax C, Maillet P, McCulloch CA, Glogauer M. How do oral health professional adopt new technologies into practice? Accepted, Journal of the American Dental Association, Feb 6, 2015.

L.A. Staudinger, S.J. Spano, W.S. Lee, N. Coelho, T.J. Moriarty, C.A. McCulloch.  Role of discoidin domain receptor 1 in dysregulation of collagen remodeling by cyclosporin A. The International Journal of Biochemistry & Cell Biology.  In Press, February 2015.

Cheung JW, Jain D, McCulloch C, Santerre P. Pro-angiogenic Character of Endothelial Cells and Gingival Fibroblasts Co-cultures in Perfused Degradable Polyurethane (D-PHI) Scaffolds. Tissue Eng Part A. 2015 Mar 10. Epub ahead of print.

Hongwei Jiang, Yongqiang Wang, Ana Viniegra, Corneliu Sima, Christopher Mcculloch, Michael Glogauer.  Adseverin Plays a Role in Osteoclast Differentiation and Function.  FASEB J. 2015 Feb 13. Epub ahead of print.

Mohammadi H, Arora PD, Simmons CA, Janmey PA, McCulloch CA. Inelastic behaviour of collagen networks in cell-matrix interactions and mechanosensation. J R Soc Interface. 2015 Jan 6;12(102).

J. Cheung, C.A. McCulloch, P. Santerre.  Establishing a Gingival Fibroblast Phenotype in a Perfused Degradable Polyurethane Scaffold: Mediation by TGF-β1, FGF-2, β1-integrin, and Focal Adhesion Kinase.  Biomaterials 35 (2014) 10025-10032.

Matthews DC, McNeil K, McCulloch CA, Glogauer M. Adoption issues associated with a new periodontal screening tool: an online survey of canadian dentists. J Can Dent Assoc. 2014 Aug;80:e57.

Richard D. Speers, Christopher A. McCulloch. Optimizing Patient Safety: Can We Learn From the Airline Industry? J Can Dent Assoc 2014;80:e37.

Bozavikov P, Rajshankar D, Lee W, McCulloch CA. Particle Size Influences Fibronectin Internalization and Degradation by Fibroblasts. Exp Cell Res. 2014 Oct 15;328(1):172-85.

Talior-Volodarsky I, Arora PD, Wang Y, Zeltz C, Connelly KA, Gullberg D, McCulloch CA.  Glycated collagen induces α11 integrin expression through TGF-β2 and Smad3. J Cell Physiol. 2014 Jun 24. doi: 10.1002/jcp.24708. Epub ahead of print.

Nogueira-Filho G, Pesun I, Ploegman C, Wijegunasinghe M, McCulloch CA. Longitudinal Comparison of Cytokines in Peri-Implant Fluid and Gingival Crevicular Fluid in Healthy Mouths. J Periodontol. 2014 Nov;85(11):1582-8.

Wang Q, Wang Y, Fritz D, Rajshankar D, Downey GP, McCulloch CA. Interactions of the protein-tyrosine phosphatase-α with the FAT domain of focal adhesion kinase are involved in IL-1 signaling in fibroblasts.  J Biol Chem. 2014 Jun 27;289(26):18427-18441.

Sandkuijl D, Kontenis L, Coelho NM, McCulloch C, Barzda V.  Interferometric backward third harmonic generation microscopy for axial imaging with accuracy beyond the diffraction limit.  PLoS One. 2014 Apr 7;9(4):e94458.

Persadmehr A, Torneck CD, Cvitkovitch DG, Pinto V, Talior I, Kazembe M, Shrestha S, McCulloch CA, Kishen A. Bioactive chitosan nanoparticles and photodynamic therapy inhibit collagen degradation in vitro.  J Endod. 2014 May;40(5):703-9.

Aschner Y, Khalifah AP, Briones N, Yamashita C, Dolgonos L, Young SK, Campbell MN, Riches DW, Redente EF, Janssen WJ, Henson PM, Sap J, Vacaresse N, Kapus A, McCulloch CA, Zemans RL, Downey GP. Protein Tyrosine Phosphatase α Mediates Profibrotic Signaling in Lung Fibroblasts through TGF-β Responsiveness.  Am J Pathol. 2014 May;184(5):1489-502.

Goicoechea SM, García-Mata R, Staub J, Valdivia A, Sharek L, McCulloch CG, Hwang RF, Urrutia R, Yeh JJ, Kim HJ, Otey CA.  Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts.  Oncogene. 2014 March 6; 33(10): 1265–1273.

Hamid Mohammadi and Christopher A McCulloch. Impact of elastic and inelastic substrate behaviors on mechanosensation. Soft Matter, 2014, 10, 408-420.

Mohammadi H, Janmey PA, McCulloch CA. Lateral boundary mechanosensing by adherent cells in a collagen gel system. Biomaterials. 2014 Jan;35(4):1138-49.

Pinto VI, Senini VW, Wang Y, Kazembe MP, McCulloch CA.  Filamin A protects cells against force-induced apoptosis by stabilizing talin- and vinculin-containing cell adhesions.  FASEB J. 2014 Jan;28(1):453-63.

Janmey PA, Wells RG, Assoian RK, McCulloch CA.  From tissue mechanics to transcription factors.  Differentiation. 2013 Oct;86(3):112-20.

Dhaarmini Rajshankar, Corneliu Sima, Qin Wang, Stephanie R. Goldberg, Mwayi Kazembe, Yongqiang Wang, Michael Glogauer, Gregory P. Downey, Christopher A. McCulloch. Role of PTPa in the Destruction of Periodontal Connective Tissues. PLoS ONE, 2013 vol. 8, issue 8, e70659.

Wang Y, Wang Q, D Arora P, Rajshankar D, McCulloch CA.  Cell adhesion proteins: roles in periodontal physiology and discovery by proteomics.  Periodontol 2000. 2013 Oct;63(1):48-58.

Bartold PM, McCulloch CA.  Information generation and processing systems that regulate periodontal structure and function.  Periodontol 2000. 2013 Oct;63(1):7-13.

Hossain GS, Lynn EG, Maclean KN, Zhou J, Dickhout JG, Lhoták S, Trigatti B, Capone J, Rho J, Tang D, McCulloch CA, Al-Bondokji I, Malloy MJ, Pullinger CR, Kane JP, Li Y, Shiffman D, Austin RC.  Deficiency of TDAG51 Protects Against Atherosclerosis by Modulating Apoptosis, Cholesterol Efflux, and Peroxiredoxin-1 Expression.  J Am Heart Assoc. 2013 May 17;2(3):e000134.

Termei R, Laschinger C, Lee W, McCulloch CA. Intercellular interactions between mast cells and fibroblasts promote pro-inflammatory signaling. Exp Cell Res. 2013 Jul 15;319(12):1839-51.

Arora PD, Wang Y, Bresnick A, Dawson J, Janmey PA, McCulloch CA.  Collagen Remodeling by Phagocytosis is determined by Collagen Substrate Topology and by Calcium-Dependent Interactions of Gelsolin with Non-Muscle Myosin IIA in Cell Adhesions.  Mol Biol Cell. 2013 Mar;24(6):734-47.

Wang Q, Siminovitch KA, Downey GP, McCulloch CA. Ras-guanine nucleotide releasing factors 1 and 2 interact with PLC? at focal adhesions to enable IL-1-induced Ca2+ signaling, ERK activation and MMP-3 expression. Biochem J. 2013 Feb 1;449(3):771-82.

Leszczynska K, Namiot D, Byfield FJ, Cruz K, Zendzian-Piotrowska M, Fein DE, Savage PB, Diamond S, McCulloch CA, Janmey PA, Bucki R. Antibacterial activity of the human host defence peptide LL-37 and selected synthetic cationic lipids against bacteria associated with oral and upper respiratory tract infections. J Antimicrob Chemother. 2013 Mar;68(3):610-8.

Schure R, Costa KD, Rezaei R, Lee W, Laschinger C, Tenenbaum HC, McCulloch CA. Impact of matrix metalloproteinases on inhibition of mineralization by fetuin. J Periodontal Res. 2013 Jun;48(3):357-66.

Li GH, Arora PD, Chen Y, McCulloch CA, Liu P. Multifunctional roles of gelsolin in health and diseases. Med Res Rev. 2012 Sep;32(5):999-1025.

Talior-Volodarsky I, Connelly KA, Arora PD, Gullberg D, McCulloch CA.  α11 integrin stimulates myofibroblast differentiation in diabetic cardiomyopathy.  Cardiovasc Res. 2012 Nov 1;96(2):265-75.

Mohammad I, Arora PD, Naghibzadeh Y, Wang Y, Li J, Mascarenhas W, Janmey PA, Dawson JF, McCulloch CA.  Flightless I is a focal adhesion-associated actin-capping protein that regulates cell migration. FASEB J. 2012 Aug;26(8):3260-72.

Rajshankar D, Downey GP, McCulloch CA.  IL-1β enhances cell adhesion to degraded fibronectin. FASEB J. 2012 Nov;26(11):4429-44.

Shifrin Y, Pinto V, Arora P, McCulloch CA. Force-induced apoptosis mediated by the Rac/PAK/p38 signaling pathway is regulated by filamin A. Biochem J. 2012 Jul 1;445 (1):57-67.

Rullo J, Becker H, Hyduk SJ, Wong JC, Digby G, Arora PD, Cano AP, Hartwig J, McCulloch CA, Cybulsky MI. Actin polymerization stabilizes α4β1-integrin anchors that mediate monocyte adhesion. J Cell Biol. 2012 Apr 2;197(1):115-29.

Park JS, Lee W, McCulloch CA. Intercellular Transfer of Apoptotic Signals via Electrofusion. Exp Cell Res. 2012 May 1;318(8):896-903.

Oystein F, McCulloch CA, McCulloch CA. Impact of Anxiety on Pain Perception Associated with Periodontal and Implant Surgery in a Private Practice. J Periodontol. 2012 Sep;83(9): 1079-85.

Greenaway JB, Koehler A, McCulloch CA, Petrik J, Brown TJ, Ringuette MJ.  The impact of the ovarian microenvironment on the anti-tumor effect of SPARC on ovarian cancer. Biochem Cell Biol. 2012 Feb;90(1):96-107.

Yamashita CM, Dolgonos L, Zemans RL, Young SK, Robertson J, Briones N, Suzuki T, Campbell MN, Gauldie J, Radisky DC, Riches DW, Yu G, Kaminski N, McCulloch CA, Downey GP. Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis. Am J Pathol. 2011 Oct;179(4):1733-45.

Zhang J, Zahir N, Jiang Q, Miliotis H, Heyraud S, Meng X, Dong B, Xie G, Qiu F, Hao Z, McCulloch CA, Keystone EC, Peterson AC, Siminovitch KA. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nat Genet. 2011 Aug 14;43(9): 902-7.

Arora PD, Wang Y, Janmey PA, Bresnick A, Yin HL, McCulloch CA. Gelsolin and non-muscle myosin IIA interact to mediate calcium-regulated collagen phagocytosis. J Biol Chem. 2011 Sep 30;286(39):34184-98.

Wang Q, Downey GP, McCulloch CA.  Focal adhesions and Ras are functionally and spatially integrated to mediate IL-1 activation of ERK. FASEB J. 2011 Oct;25(10):3448-64.

Kim H, McCulloch CA. Filamin A mediates interactions between cytoskeletal proteins that control cell adhesion. FEBS Lett. 2011 Jan 3;585(1):18-22.

Chan MW, Hinz B, McCulloch CA. Mechanical induction of gene expression in connective tissue cells. Methods Cell Biol. 2010;98:178-205.

Chan MW, Chaudary FF, Lee W, Copeland JW, McCulloch CA. Force-induced myofibroblast differentiation through collagen receptors is dependent on mammalian diaphanous (mDia). J Biol Chem. 2010 Mar 19;285(12):9273-81.

Atai NA, Bansal M, Lo C, Bosman J, Tigchelaar W, Bosch KS, Jonker A, De Witt Hamer PC, Troost D, McCulloch CA, Everts V, Van Noorden CJ, Sodek J.  Osteopontin is up-regulated and associated with neutrophil and macrophage infiltration in glioblastoma. Immunology. 2011 Jan;132(1):39-48.

Wang Q, Rajshankar D, Laschinger C, Talior-Volodarsky I, Wang Y, Downey GP, McCulloch CA.  Importance of protein-tyrosine phosphatase-alpha catalytic domains for interactions with SHP-2 and interleukin-1-induced matrix metalloproteinase-3 expression. J Biol Chem. 2010 Jul 16;285(29):22308-17.

Follonier Castella L, Gabbiani G, McCulloch CA, Hinz B. Regulation of myofibroblast activities: calcium pulls some strings behind the scene. Exp Cell Res. 2010 Sep 10;316 (15):2390-401.

Goicoechea SM, Bednarski B, Stack C, Cowan DW, Volmar K, Thorne L, Cukierman E, Rustgi AK, Brentnall T, Hwang RF, McCulloch CA, Yeh JJ, Bentrem DJ, Hochwald SN, Hingorani SR, Kim HJ, Otey CA. Isoform-specific upregulation of palladin in human and murine pancreas tumors. PLoS One. 2010 Apr 26;5(4):e10347.

Yuen A, Laschinger C, Talior I, Lee W, Chan M, Birek J, Young EW, Sivagurunathan K, Won E, Simmons CA, McCulloch CA.  Methylglyoxal-modified collagen promotes myofibroblast differentiation. Matrix Biol. 2010 Jul;29(6):537-48.

Kim H; Nakamura F, Lee W, Hong C, Pérez-Sala D, McCulloch CA. Regulation of cell adhesion to collagen via ß1 integrins is dependent on interactions of filamin A with vimentin and protein kinase C epsilon. Exp Cell Res. 2010 Jul 1;316(11):1829-44.

Kim H, Nakamura F, Lee W, Shifrin Y, Arora PD, McCulloch CA. Filamin A is required for vimentin-mediated cell adhesion and spreading. Am J Physiol Cell Physiol. 2010 Feb; 298(2):C221-36.

Appointments

Consultant for the Royal College of Dental Surgeons of Ontario (RCDSO)

Honours and Awards

Name: Career Scientist Award from the Ontario Ministry of Health (1984-1994)
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Name: Scientist Award from Columbia University (New York City)
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Name: Distinguished Scientist Award for Research in Oral Biology from the International Association of Dental Research (IADR) (2009)
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Name: Canada Research Chair (Tier 1) in Matrix Dynamics (2006-2020)
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