Education, Medical; Fibrosis; Inflammation; Lung; Respiration; T-Lymphocytes; Lung Diseases, Interstitial; Semaphorins; Biomarkers, Pharmacological; Bioengineering; Translational Medical Research
Stem Cell Center, Yale: Stem Cells and Tissue Repair | Tissue Specific Stem Cells
Work in the Herzog lab is dedicated to understanding common mechanisms promoting pulmonary fibrosis. This condition, which is characterized by the accumulation of scar tissue in the lung, is a major cause of death in Americans. We have identified a number of novel pathways that might control the development of this disease. Our studies focus on the role of Semaphorin 7a, a protein that is implicated in both brain development and inflammation, in the pathogenesis of pulmonary scar. Our lab also is performing studies of fibrosis using an artificial lung technique that was developed here at Yale. Finally, we are heavily involved in the search for predictive biomarkers that might allow physicians to identify patients with active disease and understand what separates these people from those with stable disease. It is hoped that this unique combination of translational studies will allow better insight into diseases such as Idiopathic Pulmonary Fibrosis, Scleroderma related Interstitial Lung Disease, and Sarcoidosis, with the ultimate goal of developing preventative or treatment strategies.
Specialized Terms: Pulmonary fibrosis; Semaphorins; Regulatory T cells; Plexin C1; Bioengineering
Extensive Research Description
The Herzog lab’s mission is to perform high quality translational studies aimed at elucidating common mechanism(s) of multiple forms of pulmonary fibrosis. These studies employ a unique combination of murine modeling and novel bioengineering-based approaches, as well as studies in primary human cells, that are aimed at unveiling the immunopathogenesis of human lung fibrosis.
The central focus of our laboratory is the role of Semaphorin 7a in these diseases. Semaphorin 7a (Sema 7a) is a neuronal guidance protein and immunoregulatory molecule about which little is known. In addition to its role in axon guidance, Sema 7a participates in the activation of both macrophages and lymphocytes though its precise contribution to disease remains unclear. We have found that Sema 7a promotes a profibrotic monocyte phenotype characterized by the upregulation of scavenger receptors and secretion of selected soluble mediators, as well by inducing collagen expression in these circulating cells. In fact, our work in a murine model of lung specific, doxycycline inducible TGFb1 overexpression demonstrates that hematopoetic expression of Sema 7a is sufficient to induce fibrosis in the murine lung, and that these effects are mediated at least in part via CD4+ T cells. These latter findings are quite remarkable as while CD4 cells are known to be dispensible for the development of bleomycin-induced lung fibrosis, accumulating evidence suggests that T cells might promote or suppress fibrosis in certain circumstances. Our data indicate that Sema 7a is a central mediator of these responses in the murine lung and, potentially in such diverse human diseases as IPF, Scleroderma related interstitial lung disease (SSc-ILD), and pulmonary sarcoidosis. Current studies in this area are aimed at clarifying the role of Sema 7a’s receptors (CD29 and Plexin C1) as well as other Sema 7a related molecules and signaling pathways in these processes.
Another important area of Dr. Herzog’s work involves the application of bioengineering based strategies to the study of lung fibrosis. As part of the first team to develop a bioartificial lung based on decellularized rat lung scaffolds suitable for in vivo implantation, Dr. Herzog has spent the last few years modifying these scaffolds for use in murine and human modeling systems and now has in place a dedicated scaffold based system that can support the growth of cell lines or primary. This approach is ideal in its ability to enable the studies of cell:matrix interactions.Last, perhaps most reflecting Dr. Herzog’s training as a physician scientist, the lab is also leading the search for predictive peripheral blood biomarkers of disease activity in IPF, SSc-ILD, and sarcoidosis. As a member of the NIH funded MAPGEN and GRADS consortiums, the Herzog lab collaborates with physician scientists across the country to recruit, characterize, and immunophenotype peripheral blood samples from patients with a wide variety of fibrosing diseases.
Semaphorin 7a and its downstream signaling pathways in the immunopathology of pulmonary fibrosis
Application of bioengineering strategies to lung biology
Development of peripheral blood biomarkers of disease activity in IPF, SSc-ILD and sarcoidosis
- Mathai S. K. and Herzog EL. Fibrocytes in Scleroderma Lung Disease in Fibrocytes: New insights into tissue repair and systemic fibroses. World Scientific Publishing Co. Singapore 2012 in press.
- Murray LA, Rubinowitz AS, Herzog EL. Interstitial Lung Disease: Are IPF and Scleroderma ILD the same disease? Curr Op Rheum 2012 in press.
- Mathur AM, Herzog EL. Sticking it to fibrocytes with serum amyloid P. J Leuk Bio 2012 in press.
- Dunmore R, Carruthers AM, Bell MJ, Zhang H, Hogaboam CM, Herzog EL, Knight DA, Martinez FJ, Sleeman MA, Murray LA. An Assessment of Epithelial and Mesenchymal Phenotypes in Experimental and Clinical Pulmonary Fibrosis. ISRN Pulmonology in press 2012.
- Lee CG, Herzog EL*, Ahangari F, Varga J, Feghali-Bostwick C, Jimenez S, Peng X, Gulati MS, Elias JA. Chit1 as a biomarker and disease mediator in Systemic Sclerosis Associated Lung Disease. Journal of Immunology in press, 2012. *co-first author
- Lee CG, Dela Cruz CS, Herzog EL, Rosenberg SM, Ahangari F, Elias JA. YKL-40, a chitinase-like protein at the intersection of inflammation and remodeling. Am J Respir Crit Care Med. 2012 Apr 1;185(7):692-4.
- Peng X, Mathai S, Murray LM, Russell TR, Reilkoff RA, Chen Q, Elias JA, Bucala RJ, Homer RJ, Herzog EL. Local apoptosis promotes collagen production in monocyte derived cells. Fibrogenesis and Tissue Repair 2011 May 17;4(1):12. PMID:21586112; PMCID: PMC
- Gan Y, Reilkoff RA, Peng XY, Russell TR, Chen QC, Mathai SK, Gulati M, Homer RJ, Elias, JA, Bucala RJ, and Herzog EL. Role of Semaphorin 7a in TGF?1-induced lung fibrosis, fibrocyte differentiation, and scleroderma-related interstitial lung disease. Arth Rheum 2011. Aug 63(8):2484-94. PMID:21484765
- Murray LM, Chen QC, Kramer MS, Hesson DM, Argentieri RL, Peng X, Gulati M, van Rooijen NR, Homer RJ, Elias JA, Hogaboam CM and Herzog EL. Serum Amyloid P Inhibits TGF?- Driven Lung Fibrosis. Int J Biochem Cell Biol. 2011 Jan;43(1):154-62 PMID 21044893.
- Petersen T, Calle E, Zhao L, Lee EJ, Gui L, Raredon MS, Gavrilov K, Herzog EL, and Niklason L. Bioengineered lung for in vivo implantation. Science 2010 Jul; 329:538-41.
- Murray LM, Rosada R, Moreira AP, Joshi A, Kramer M, Hesson D, Argentieri R, Mathai SK, Herzog EL, Hogaboam C. Serum Amyloid P Therapeutically Attenuates Murine Bleomycin-Induced Pulmonary Fibrosis Via Its Effects on Macrophages. PLoS One. 2010 Mar 12;5(3):e9683.PMID 20300636.
- Mathai SK, G. M., Peng XY, Gan Y, Siner JM, Antin-Ozerkis DE, Bucala RJ, Herzog EL Circulating Monocytes from Systemic Sclerosis Patients with Interstitial Lung Disease Show an Enhanced Profibrotic Phenotype. Lab Inv 90 (6) 182-23, 2010.
- Mathai SK, Rubinowitz AN, Homer RJ, Detterbeck F, Herzog EL. Of lungs, lipids, and lollipops. Chest 2009;136(5):1420-3.
- Franks TJ, Colby TV, Travis WD, Tuder RM, Reynolds HY, Brody AR, Cardoso WV, Crystal RG, Drake CJ, Engelhardt J, Frid M, Herzog EL, Mason R, Phan SH, Randell SH, Rose MC, Stevens T, Serge J, Sunday ME, Voynow JA, Weinstein BM, Whitsett J, Williams MC. Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function. 2008. Proc Am Thorac Soc 5(7):763-6.
- Herzog EL, Brody AR, Colby TV, Mason R, Williams MC. Knowns and unknowns of the alveolus. 2008. Proc Am Thorac Soc 5(7):778-82.
- Stevens T, Phan S, Frid MG, Alvarez D, Herzog EL, Stenmark KR. Lung vascular cell heterogeneity: endothelium, smooth muscle, and fibroblasts. 2008. Proc Am Thorac Soc 5(7):783-91.
- Herzog EL, Van Arnam J, Hu B, Zhang J, Chen Q, Haberman AM, Krause DS. Lung-specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation. Faseb J, 2007 21(10):2592-601.
- Herzog EL, Van Arnam J, Hu B, Krause DS. Threshold of lung injury required for the appearance of marrow-derived lung epithelia. Stem Cells, 2006, 24(8):1986-92.
- Borue, X., Lee, S., Grove, J., Herzog, E.L., Harris, R., Diflo, T., Glusac, E., Hyman, K., Theise, N.D., and Krause, D.S. 2004. Bone Marrow-Derived Cells Contribute to Epithelial Engraftment during Wound Healing. Am J Pathol 165:1767-1772.
- Harris RG*, Herzog EL*,Grove JE, Bruscia EM, VanArnam JS, Krause DS. Lack of a fusion requirement for development of bone marrow derived epithelium. Science, 2004, 305 (5680): 90-93. *co-first author
- Herzog EL, Chai L, Krause DS. Plasticity of marrow derived stem cells. Blood, 2003, 102(10): 3483-93.
- Wagner TE Herzog EL, Frevert CM, Schnapp LM. Expression of the integrin subunit alpha8beta1 in murine lung development. J Histochem Cytochem, 2003, 51(10):1307-15.