Madeline Cramer 

Madeline Cramer

Faculty Mentor: Stephen Badylak

Research:

Ms. Cramer’s project looks at the role of ECM-associated IL-33 in functional cardiac repair. Fibrosis occurs when cardiac myocytes damaged by ischemia are replaced by fibroblasts that produce excessive extracellular matrix (ECM). Increased stiffness of fibrotic myocardial tissue leads to heart failure. Decellularized ECM has been used as both a solid sheet and an injectable hydrogel to promote constructive remodeling of cardiac tissue. The precise mechanisms by which ECM directs cardiac tissue repair are only partially understood, but the ability of ECM to activate macrophages toward a pro-remodeling phenotype is thought to play a role. The recent identification of matrix bound nanovesicles (MBV) embedded within the ECM provides potential insight into the mechanisms behind the inductive properties of ECM materials. We have discovered that MBV derived from ECM are a rich source of extra-nuclear interleukin-33 (IL-33). IL-33 is a member of the IL-1 family of cytokines and has been classified as an “alarmin”, though there are conflicting reports of pro- versus anti-inflammatory effects. IL-33 is critical to control of early inflammation and tissue repair after acute chemical injury in the lungs and prevents chronic rejection-associated transplant fibrosis.

MBV isolated from wildtype (il33+/+) and IL-33 deficient (il33-/-) mice will be used to identify the potential role of IL-33 in immunomodulation and constructive remodeling of cardiac tissue. MBV from wildtype (il33+/+) mice activated macrophages toward a pro-remodeling M2-like phenotype through a non-canonical ST2 receptor-independent pathway, while il33-/- MBV promoted a pro-inflammatory M1-like phenotype in st2-/- macrophages. The direct effect of IL-33 on cardiac fibroblast and cardiomyocyte phenotype will be determined following exposure to MBV from wildtype or IL-33 deficient mice. The secretome of st2-/- macrophages treated with wildtype or IL-33 deficient MBV will also be used to determine indirect effect of immunomodulation on the relevant cardiac cells. Identification of IL-33 as a critical mediator of early repair processes would guide development for a new generation of extracellular matrix-based therapies for cardiac tissue repair.

Publications:

  • Hussey, G. S., Cramer, M. C. & Badylak, S. F. Extracellular Matrix Bioscaffolds for Building Gastrointestinal Tissue. Cell. Mol. Gastroenterol. Hepatol.5, 1–13 (2017).
  • Huleihel, L., Dziki, J.L., Bartolacci, J.G., Rausch, T., Scarriett, M.E., Cramer, M.C., Vorobyov, T., LoPresti, S.T, Swineheart, I.T., White, L.J., Brown, B.N., & Badylak, S.F. Macrophage phenotype in response to ECM bioscaffolds. Semin. Immunol.29, 2–13 (2017).
  • Cramer, M.C.*, Saldin, L. T.*, Cramer, M. C., Velankar, S. S., White, L. J. & Badylak, S. F. Extracellular matrix hydrogels from decellularized tissues: Structure and function. Acta Biomater.49, 1–15 (2017). [*co-first author]
  • Dziki, J. L., Sicari, B. M., Wolf, M. T., Cramer, M. C. & Badylak, S. F. Immunomodulation and Mobilization of Progenitor Cells by Extracellular Matrix Bioscaffolds for Volumetric Muscle Loss Treatment. Tissue Eng. Part A22, ten.TEA.2016.0340 (2016).
  • Ninh, C., Iftikhar, A., Cramer, M.C. & Bettinger, C. J. Diffusion-reaction models of genipin incorporation into fibrin networks. J. Mater. Chem. B3, 4607–4615 (2015).
  • Ninh, C., Cramer, M.C. & Bettinger, C. J. Photoresponsive hydrogel networks using melanin nanoparticle photothermal sensitizers. Biomater. Sci.2, 766 (2014).

Conferences:

  • Cramer, M.C., Dziki, J., Hussey, G., Turnquist, H.R., & Badylak, S.F. Role of ECM-Associated IL-33 in Functional Cardiac Repair. Podium presentation. 2018. Future Investigators of Regenerative Medicine Symposium.
  • Cramer, M.C., Pineda Molina, C., Quijano, L.M., Khurana, N., & Badylak, S.F. Role of miR- 143/145 in ECM-Based Therapy for Ulcerative Colitis. Poster presentation. 2018. Biologic Scaffolds for Regenerative Medicine Symposium.
  • Cramer, M.C., Dziki, J., Hussey, G., Turnquist, H.R. & Badylak, S.F. Role of ECM-associated IL-33 in Functional Cardiac Repair. Poster presentation. 2018. McGowan Institute for Regenerative Medicine Retreat.
  • Cramer, M.C., Pineda Molina, C.P., Quijano, L.M., & Badylak, S.F. An Acellular Regenerative Medicine Approach for Ulcerative Colitis. Podium presentation. 2017. TERMIS-AM Annual Meeting.