Center for Molecular Medicine Cologne

Sengle, Gerhard - assoc. RG 21

New molecular mechanisms of fibrosis

Abstract

Fibrosis is characterized by excess accumulation of extracellular matrix (ECM) components, leading to disrupted tissue function in affected organs. Fibrosis can develop in nearly every part of the body, and is an important driver of end-stage organ failure and death in a variety of chronic diseases. The high number of individuals affected by organ fibrosis and the associated morbidity and mortality shows the need for a better understanding of mechanisms involved in fibroblast activation and abnormal ECM deposition.

For the development of new therapeutic strategies to prevent or treat fibrotic disease it is mandatory to understand how individual ECM components integrate communication with the cell surface by presenting growth factors or providing fine-tuned biomechanical properties. In particular, the important role of epithelial–mesenchymal interactions in fibrosis needs to be elucidated. The goal of this proposal is to gain insight into newly uncovered molecular mechanisms of fibrotic reactions. We will specifically address the question how dysregulated epidermal-dermal communication is cause or consequence of fibrotic reactions.

Data from mouse models reflecting human fibrotic conditions revealed new critical determinants, including failed epidermal collagen chaperoning as well as TGF-β and lysyl oxidase ECM targeting. This proposal aims at providing a new understanding of the underlying molecular causes of fibrotic reactions which will lay the foundation for future translational approaches.

Clinical and Medical Relevance

Fibrosis is an important driver of organ failure and death. Despite intensive research, many aspects of the molecular causes of fibrosis remain unclear. Therefore, it is important to elucidate the molecular determinants crucial in the initiating steps of the disease.

By investigating new mouse models for organ fibrosis as well as corresponding patient cells in combination with structural and pharmacological approaches we will explore new therapeutic avenues to prevent or treat fibrotic disease.

  1. Zigrino P, and Sengle G. Fibrillin microfibrils and proteases, key integrators of fibrotic pathways. Adv Drug Deliv Rev. (2019) 146:3-16.
  2. Schiavinato A, Keene DR, Imhof T, Doliana R, Sasaki T, Sengle G. Fibulin-4 deposition requires EMILIN-1 in the extracellular matrix of osteoblasts. Sci Rep. (2017) 7, 5526.
  3. Brauchle E, Bauer H, Fernes P, Zuk A, Schenke-Layland K, Sengle G. Raman microspectroscopy as a diagnostic tool for the non-invasive analysis of fibrillin-1 deficiency in the skin and in the in vitro skin models. Acta Biomater. (2017) 52, 41-48.
  4. Sengle G, Sakai LY. The fibrillin microfibril scaffold: A niche for growth factors and mechanosensation? Matrix Biol, 2015, 47, 3-12.
  5. Wohl AP, Troilo H, Zuk AV, Collins R, Baldock C, Sengle G. Extracellular regulation of BMP activity by the microfibril component fibrillin-1. J Biol Chem. (2016) 291, 12732-46.
  6. Schiavinato A, Keene DR, Wohl AP, Corallo D, Colombatti A, Wagener R, Paulsson M, Bonaldo P, Sengle G. Targeting of EMILIN-1 and EMILIN-2 to fibrillin microfibrils facilitates their incorporation into the extracellular matrix. J Invest Dermatol. (2016) 136, 1150-1160.
  7. Sengle G, Carlberg V, Tufa SF, Charbonneau NL, Smaldone S, Carlson EJ, Ramirez F, Keene DR, Sakai LY. Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice. PLoS Genet. (2015) 11, e1005340.
  8. Sengle G, Tsutsui K, Keene DR, Tufa SF, Carlson EJ, Charbonneau NL, Ono RN, Sasaki T, Wirtz MK, Samples JR, Fessler LI, Fessler JH, Sekiguchi K, Hayflick SJ, Sakai LY. Microenvironmental regulation by fibrillin-1. PLoS Genet (2012) 8, e1002425.
                                                                                                                  • Akasaka E, Kleiser S, Sengle G, Bruckner-Tuderman L, Nyström A (2021). Diversity of Mechanisms Underlying Latent TGF-β Activation in Recessive Dystrophic Epidermolysis Bullosa. J Invest Dermatol141, 1450-1460.e9. doi: 10.1016/j.jid.2020.10.024.
                                                                                                                  • Furlan AG, Spanou CES, Godwin ARF, Wohl AP, Zimmermann LA, Imhof T, Koch M, Baldock C, and Sengle G (2021). A new MMP-mediated prodomain cleavage mechanism to activate bone morphogenetic proteins from the extracellular matrix. FASEB J35, e21353. doi:10.1096/fj.202001264R.
                                                                                                                  • Pottie L, Adamo CS, Beyens A, Lutke S, Tapaneeyaphan P, De Clercq A, Salmon PL, De Rycke R, Gezdirici A, Gulec EY, Khan N, Urquhart JE, Newman WG, Metcalfe K, Efthymiou S, Maroofian R, Anwar N, Maqbool S, Rahman F, Altweijri I, Alsaleh M, Abdullah SM, Al-Owain M, Hashem M, Houlden H, Alkuraya FS, Sips P, Sengle G, and Callewaert B (2021). Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome. Am J Hum Genet108, 1095-1114. doi:10.1016/j.ajhg.2021.04.016.
                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Welcker D, Stein C, Feitosa NM, Armistead J, Zhang JL, Lutke S, Kleinridders A, Bruning JC, Eming SA, Sengle G, Niehoff A, Bloch W, and Hammerschmidt M (2021). Hemicentin-1 is an essential extracellular matrix component of the dermal-epidermal and myotendinous junctions. Sci Rep11, 17926. doi:10.1038/s41598-021-96824-4.
                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Adamo CS, Zuk AV, and Sengle G (2021). The fibrillin microfibril/elastic fibre network: A critical extracellular supramolecular scaffold to balance skin homoeostasis. Exp Dermatol30, 25-37. doi:10.1111/exd.14191.
                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Correns A, Zimmermann LA, Baldock C, and Sengle G (2021). BMP antagonists in tissue development and disease. Matrix Biol Plus11, 100071. doi:10.1016/j.mbplus.2021.100071.
                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Zimmermann LA, Correns A, Furlan AG, Spanou CES, and Sengle G (2021). Controlling BMP growth factor bioavailability: The extracellular matrix as multi skilled platform. Cell Signal85, 110071. doi:10.1016/j.cellsig.2021.110071.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Etich J, Rehberg M, Eckes B, Sengle G, Semler O, and Zaucke F (2020). Signaling pathways affected by mutations causing osteogenesis imperfecta. Cell Signal 76, 109789.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Imhof T, Korkmaz Y, Koch M, Sengle G, and Schiavinato A (2020a). EMILIN proteins are novel extracellular constituents of the dentin-pulp complex. Sci Rep 10, 15320.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Janoschek R, Hoffmann T, Morcos YAT, Sengle G, Dotsch J, and Hucklenbruch-Rother E (2020). Asprosin in pregnancy and childhood. Molecular and cellular pediatrics 7, 18.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Kohler A, Morgelin M, Gebauer JM, Ocal S, Imhof T, Koch M, Nagata K, Paulsson M, Zaucke F, Baumann U, and Sengle G (2020). New specific HSP47 functions in collagen subfamily chaperoning. FASEB J 10.1096/fj.202000570R.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Prof. Dr. Gerhard Sengle CMMC Cologne
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Prof. Dr. Gerhard Sengle

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Center for Biochemistry

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    CMMC - assoc. RG 21

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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Center for Biochemistry

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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Publications - Gerhard Sengle

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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Group Members

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Dr. Katrin Hildebrandt
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Christin Adamo
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Chara Spanou
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Laura-Marie Zimmermann
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Annkatrin Correns
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Steffen Lütke
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Yousef Morcos