• The mechanics of leukocyte extravasation and subsequent migration through the three-dimensional extracellular matrix

  • miércoles, 27 junio
  • Centro de Tecnología Biomédica Salón de actos
  • Prof. Juan Carlos del Álamo. University of California, San Diego.

    Leukocyte transmigration across vessel walls is a critical step in the immune response. Upon their activation and firm adhesion to vascular endothelial cells (VECs), leukocytes cross junctional gaps in the endothelial monolayer (paracellular diapedesis). It has been hypothesized that VECs facilitate diapedesis by opening their cell-cell junctions in response to an adhering leukocyte. However, it is unclear how leukocytes interact mechanically with VECs to open the VEC junctions and migrate across the endothelium. We measured the 3D traction stresses generated by the leukocytes and VECs to elucidate the sequence of mechanical events involved in paracellular diapedesis.  Decoupling the stresses exerted by the leukocytes and the VECs reveals that the leukocytes actively contract the VECs to open a junctional gap, and then push themselves across the gap by generating strong stresses that push into the matrix. In addition, we found that diapedesis is facilitated when the tension fluctuations in the VEC monolayer were increased by pro-inflammatory agents. Our findings demonstrate that diapedesis can be mechanically regulated by the transmigrating leukocytes and by pro-inflammatory signals that increase VEC contractility.

    Upon extravasation, leukocytes migrate through fibrous 3-D matrices. To study the mechanics of this process, we are investigating 3-D leukocyte motility in collagen matrices of different concentrations using custom built microfluidic devices.  Particle Image Velocimetry and Finite Deformation Theory are used to compute displacement fields in the collagen matrices. Stress fields in the matrices were computed using our E3DFM method. We will present data showing that morphological changes and migratory patterns vary depending on the porosity of the collagen matrices. We will also provide data showing a clear relationship between the aforementioned migratory characteristics and computed displacement and stress fields around migrating leukocytes. The results from our study show that neutrophils migrating in 3-D environments employ distinct mechanical mechanisms that depend on the structure of their mechanical environments.

    Brief CV:

    Prof. del Alamo received a B.S., M.S. and Ph. D. in Aerospace Engineering at the Polytechnic University in Madrid. He was a Fulbright postdoctoral fellow at Harvard University and UC Sand Diego, where he received training in experimental cell mechanics and cardiovascular flows. Prof. del Alamo’s lab at UCSD focuses on biological fluid mechanics and cardiovascular physiology, with particular emphasis on cellular biomechanics and non-invasive characterization of intracardiac flows. This research has been recognized with awards such as the US Geological Survey Director’s Award (2010), the NSF CAREER Award (2011) and the William Parmley Award from American College of Cardiology (2015).