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.
Interstitial Lung Disease: Are IPF and Scleroderma ILD the same disease?
Murray LA, Rubinowitz AS, Herzog EL. Interstitial Lung Disease: Are IPF and Scleroderma ILD the same disease? Curr Op Rheum 2012 in press.
Editorial: Sticking it to fibrocytes with serum amyloid P.
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.
Chit1 as a biomarker and disease mediator in Systemic Sclerosis Associated Lung Disease.
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
YKL-40, a chitinase-like protein at the intersection of inflammation and remodeling.
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.
Local apoptosis promotes collagen production in monocyte derived cells. Fibrogenesis and Tissue Repair
Peng X, Mathai S, Murray LM, Russell TR, Reilkoff RA, Chen Q, Elias JA, Bucala RJ, Homer RJ, Herzog EL. Fibrogenesis Tissue Repair. 2011 May 17;4(1):12. doi: 10.1186/1755-1536-4-12.
Role of semaphorin 7a signaling in transforming growth factor β1-induced lung fibrosis and scleroderma-related interstitial lung disease.
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
TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P.
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.
Tissue-engineered lungs for in vivo implantation.
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.
Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages.
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.
Circulating Monocytes from Systemic Sclerosis Patients with Interstitial Lung Disease Show an Enhanced Profibrotic Phenotype.
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.
Of lungs, lipids, and lollipops.
Mathai SK, Rubinowitz AN, Homer RJ, Detterbeck F, Herzog EL. Of lungs, lipids, and lollipops. Chest 2009;136(5):1420-3.
Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function.
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.
Knowns and unknowns of the alveolus.
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.
Lung vascular cell heterogeneity: endothelium, smooth muscle, and fibroblasts.
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.
Lung-specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation.
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.
Threshold of lung injury required for the appearance of marrow-derived lung epithelia.
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.
Bone Marrow-Derived Cells Contribute to Epithelial Engraftment during Wound Healing.
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.
Lack of a fusion requirement for development of bone marrow derived epithelium.
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
Plasticity of marrow derived stem cells.
Herzog EL, Chai L, Krause DS. Plasticity of marrow derived stem cells. Blood, 2003, 102(10): 3483-93.
Expression of the integrin subunit alpha8beta1 in murine lung development.
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.
Full List of PubMed Publications
- Tzouvelekis A, Herazo-Maya JD, Slade M, Chu JH, Deiuliis G, Ryu C, Li Q, Sakamoto K, Ibarra G, Pan H, Gulati M, Antin-Ozerkis D, Herzog EL, Kaminski N: Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis. Respirology. 2017 Apr; 2016 Oct 19. PMID: 27761978
- Tzouvelekis A, Yu G, Lino Cardenas CL, Herazo-Maya JD, Wang R, Woolard T, Zhang Y, Sakamoto K, Lee H, Yi JS, DeIuliis G, Xylourgidis N, Ahangari F, Lee PJ, Aidinis V, Herzog EL, Homer R, Bennett AM, Kaminski N: SH2 Domain-Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis. Am J Respir Crit Care Med. 2017 Feb 15. PMID: 27736153
- Ryu C, Herzog EL, Pan H, Homer R, Gulati M: Upper Airway Obstruction Requiring Emergent Tracheostomy Secondary to Laryngeal Sarcoidosis: A Case Report. Am J Case Rep. 2017 Feb 13; 2017 Feb 13. PMID: 28190872
- Peng X, Moore M, Mathur A, Zhou Y, Sun H, Gan Y, Herazo-Maya JD, Kaminski N, Hu X, Pan H, Ryu C, Osafo-Addo A, Homer RJ, Feghali-Bostwick C, Fares WH, Gulati M, Hu B, Lee CG, Elias JA, Herzog EL: Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis. FASEB J. 2016 Dec; 2016 Sep 8. PMID: 27609773
- Moore MW, Herzog EL: Regulatory T Cells in Idiopathic Pulmonary Fibrosis: Too Much of a Good Thing? Am J Pathol. 2016 Aug; 2016 Jun 23. PMID: 27344432
- Fares WH, Bellumkonda L, Tonelli AR, Carson SS, Hassoun PM, Trow TK, Herzog EL, Kaminski N, Kholdani CA, Zhang L, Zhou Y, Hammel JP, Dweik RA: Right atrial pressure/pulmonary artery wedge pressure ratio: A more specific predictor of survival in pulmonary arterial hypertension. J Heart Lung Transplant. 2016 Jun; 2016 Jan 8. PMID: 26856665
- Ma B, Herzog EL, Moore M, Lee CM, Na SH, Lee CG, Elias JA: RIG-like Helicase Regulation of Chitinase 3-like 1 Axis and Pulmonary Metastasis. Sci Rep. 2016 May 20; 2016 May 20. PMID: 27198666
- Ryu C, Homer RJ, Herzog EL: The Airway in Idiopathic Pulmonary Fibrosis: Protecting the Lung or Promoting Disease? Am J Respir Crit Care Med. 2016 May 15. PMID: 27174477
- Sun H, Zhu Y, Pan H, Chen X, Balestrini JL, Lam TT, Kanyo JE, Eichmann A, Gulati M, Fares WH, Bai H, Feghali-Bostwick CA, Gan Y, Peng X, Moore MW, White ES, Sava P, Gonzalez AL, Cheng Y, Niklason LE, Herzog EL: Netrin-1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin-Induced Pulmonary Fibrosis. Arthritis Rheumatol. 2016 May. PMID: 26749424
- Southern BD, Grove LM, Rahaman SO, Abraham S, Scheraga RG, Niese KA, Sun H, Herzog EL, Liu F, Tschumperlin DJ, Egelhoff TT, Rosenfeld SS, Olman MA: Matrix-driven Myosin II Mediates the Pro-fibrotic Fibroblast Phenotype. J Biol Chem. 2016 Mar 18; 2016 Jan 13. PMID: 26763235
- Calle EA, Mendez JJ, Ghaedi M, Leiby KL, Bove PF, Herzog EL, Sundaram S, Niklason LE: Fate of distal lung epithelium cultured in a decellularized lung extracellular matrix. Tissue Eng Part A. 2015 Jun; 2015 May 4. PMID: 25789725
- Ma B, Herzog EL, Lee CG, Peng X, Lee CM, Chen X, Rockwell S, Koo JS, Kluger H, Herbst RS, Sznol M, Elias JA: Role of chitinase 3-like-1 and semaphorin 7a in pulmonary melanoma metastasis. Cancer Res. 2015 Feb 1; 2014 Dec 15. PMID: 25511377
- Hu X, DeBiasi EM, Herzog EL: Flow Cytometric Identification of Fibrocytes in the Human Circulation. Methods Mol Biol. 2015. PMID: 26420706
- Herzog EL, Mathur A, Tager AM, Feghali-Bostwick C, Schneider F, Varga J: Review: interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: how similar and distinct? Arthritis Rheumatol. 2014 Aug. PMID: 24838199
- Zhou Y, Peng H, Sun H, Peng X, Tang C, Gan Y, Chen X, Mathur A, Hu B, Slade MD, Montgomery RR, Shaw AC, Homer RJ, White ES, Lee CM, Moore MW, Gulati M, Lee CG, Elias JA, Herzog EL: Chitinase 3-like 1 suppresses injury and promotes fibroproliferative responses in Mammalian lung fibrosis. Sci Transl Med. 2014 Jun 11. PMID: 24920662
- Peng X, Moore MW, Peng H, Sun H, Gan Y, Homer RJ, Herzog EL: CD4+CD25+FoxP3+ Regulatory Tregs inhibit fibrocyte recruitment and fibrosis via suppression of FGF-9 production in the TGF-β1 exposed murine lung. Front Pharmacol. 2014 May 16; 2014 May 16. PMID: 24904415
- Sun H, Calle E, Chen X, Mathur A, Zhu Y, Mendez J, Zhao L, Niklason L, Peng X, Peng H, Herzog EL: Fibroblast engraftment in the decellularized mouse lung occurs via a β1-integrin-dependent, FAK-dependent pathway that is mediated by ERK and opposed by AKT. Am J Physiol Lung Cell Mol Physiol. 2014 Mar 15; 2013 Dec 13. PMID: 24337923
- Gan Y, Herzog EL: MMP28 and macrophage polarization: orchestrating the attack of the mac. J Leukoc Biol. 2014 Jan. PMID: 24385575
- Moore MW, Herzog EL: Regulation and Relevance of Myofibroblast Responses in Idiopathic Pulmonary Fibrosis. Curr Pathobiol Rep. 2013 Sep. PMID: 25705577
- He CH, Lee CG, Dela Cruz CS, Lee CM, Zhou Y, Ahangari F, Ma B, Herzog EL, Rosenberg SA, Li Y, Nour AM, Parikh CR, Schmidt I, Modis Y, Cantley L, Elias JA: Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor α2. Cell Rep. 2013 Aug 29; 2013 Aug 22. PMID: 23972995
- Reilkoff RA, Peng H, Murray LA, Peng X, Russell T, Montgomery R, Feghali-Bostwick C, Shaw A, Homer RJ, Gulati M, Mathur A, Elias JA, Herzog EL: Semaphorin 7a+ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-β1-induced pulmonary fibrosis. Am J Respir Crit Care Med. 2013 Jan 15; 2012 Dec 6. PMID: 23220917
- Lee CG, Herzog EL, Ahangari F, Zhou Y, Gulati M, Lee CM, Peng X, Feghali-Bostwick C, Jimenez SA, Varga J, Elias JA: Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-β1 signaling. J Immunol. 2012 Sep 1; 2012 Jul 23. PMID: 22826322
- Russell TM, Herzog EL, Bucala R: Flow cytometric identification of fibrocytes in scleroderma lung disease. Methods Mol Biol. 2012. PMID: 22933077
- Reilkoff RA, Bucala R, Herzog EL: Fibrocytes: emerging effector cells in chronic inflammation. Nat Rev Immunol. 2011 Jun; 2011 May 20. PMID: 21597472
- Peng X, Mathai SK, Murray LA, Russell T, Reilkoff R, Chen Q, Gulati M, Elias JA, Bucala R, Gan Y, Herzog EL: Local apoptosis promotes collagen production by monocyte-derived cells in transforming growth factor β1-induced lung fibrosis. Fibrogenesis Tissue Repair. 2011 May 17; 2011 May 17. PMID: 21586112
- Homer RJ, Herzog EL: Recent advances in pulmonary fibrosis: implications for scleroderma. Curr Opin Rheumatol. 2010 Nov. PMID: 20693906
- Herzog EL, Bucala R: Fibrocytes in health and disease. Exp Hematol. 2010 Jul; 2010 Mar 18. PMID: 20303382
- Mathai SK, Gulati M, Peng X, Russell TR, Shaw AC, Rubinowitz AN, Murray LA, Siner JM, Antin-Ozerkis DE, Montgomery RR, Reilkoff RA, Bucala RJ, Herzog EL: Circulating monocytes from systemic sclerosis patients with interstitial lung disease show an enhanced profibrotic phenotype. Lab Invest. 2010 Jun; 2010 Apr 19. PMID: 20404807
- Mathai SK, Rubinowitz AN, Homer RJ, Detterbeck F, Herzog EL: Of lungs, lipids, and lollipops. Chest. 2009 Nov. PMID: 19892683
- Herzog EL, Brody AR, Colby TV, Mason R, Williams MC: Knowns and unknowns of the alveolus. Proc Am Thorac Soc. 2008 Sep 15. PMID: 18757317
- 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 Aug; 2007 Apr 20. PMID: 17449722
- Herzog EL, Krause DS: Engraftment of marrow-derived epithelial cells: the role of fusion. Proc Am Thorac Soc. 2006 Nov. PMID: 17065375
- 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 Aug. PMID: 16868209
- Borue X, Lee S, Grove J, Herzog EL, Harris R, Diflo T, Glusac E, Hyman K, Theise ND, Krause DS: Bone marrow-derived cells contribute to epithelial engraftment during wound healing. Am J Pathol. 2004 Nov. PMID: 15509544
- Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS: Lack of a fusion requirement for development of bone marrow-derived epithelia. Science. 2004 Jul 2. PMID: 15232107
- Herzog EL, Chai L, Krause DS: Plasticity of marrow-derived stem cells. Blood. 2003 Nov 15; 2003 Jul 31. PMID: 12893756