BMP signaling in a biomechanical context

A: Bone cells moving around on a culture surface by rearranging their cytoskeleton. B: Fluid flow leads to calcium influx into the cytoplasm. C: Mesenchymal cells migrate on soft hydrogels in a wound healing assay. (click image to play)

A: Bone cells moving around on a culture surface by rearranging their cytoskeleton. B: Fluid flow leads to calcium influx into the cytoplasm. C: Mesenchymal cells migrate on soft hydrogels in a wound healing assay. (click image to play)

Bone Morphogenetic Proteins (BMPs) are important regulators in a multitude of cellular processes and their signaling pathway is tightly controlled by a regulatory network including not only biochemical factors but also mechanical cues. The abundance of mechanical forces in the body contributes to shaping and homeostasis of many tissues and cell types, such as endothelial cells, osteoblasts or muscle cells. Mechanical signals that control cell fate decisions may comprise active forces, such as compressive or shear forces, but may also be encoded by substrate characteristics like stiffness, geometry or ligand spacing.

The Knaus Lab investigates the interplay between BMP signaling and mechanotransduction mainly in three contexts: bone development and metabolism, physiological and pathological blood flow in the vascular system, and instruction of mesenchymal progenitors by mechanical signals encoded in the extracellular matrix. To address our research questions we apply several bioreactor- and biomaterial-based cell culture systems that allow the modulation of the mechanical microenvironment. We in particular aim to unravel the molecular principles integrating mechanical signals into BMP signaling cascades and focus on their physiological outcome in different cell systems. Specifically we are interested in crosstalks of BMP signaling to the cytoskeleton, adhesion sites, ion channels, and the cilium, as well as defining the role of the BMP receptors in mechanoresponsiveness of the cell. Further, we use hydrogel-based culture system to analyze how substrate properties such as stiffness, ligand presentation and integrin-ECM interactions shape the cellular response on a molecular and functional level.

A more detailed understanding of this crosstalk in respect to molecular interactions will be indispensable in the future, in particular to understand BMP-related diseases as well as with regard to an efficient clinical application of BMP ligands.


Methods:

  • 2D and 3D culture of cells on substrates with varying stiffness, architecture, and biochemical functionalization
  • High resolution microscopy of fixed and living cells
  • Bioreactor systems to apply compressive and shear forces of different magnitudes
  • Proteinbiochemical and expression analyses of cellular responses to different mechanical inputs

Collaboration partners:

  • Dr. Ansgar Petersen, Zelluläre Biomechanik, Julius Wolff Institut für Biomechanik und Muskuloskeletale Regeneration, Charite, Berlin
  • Associate Professor of Pediatrics Prof. Dr. Hans-Georg Simon, Stanley Manne Children's Research Institute, Northwestern University, Chicago
  • Prof. Dr. Carsten Werner, Institute of Biofunctional Polymer Materials, Leibniz-Institut für Polymerforschung e.V. Dresden

Funding:

  • Forschergruppe 2165 – Regeneration in Aged
  • Berlin Brandenburg School for Regenerative Therapies