The Department of Biomedicine

CCBIO seminar: Boris Hinz

Myofibroblasts can have it all: matrix mechanics, integrins, and pro-fibrotic growth factor activation

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Boris Hinz
Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, University of Toronto, Canada

Tissues lose their integrity upon injury. To rapidly restore mechanical stability, a variety of different cell types are activated to acquire a reparative phenotype – the myofibroblast. Hallmarks of the myofibroblast are secretion of extracellular matrix (ECM), development of adhesion structures with the ECM, and formation of actomyosin contractile stress fibers. Rapid repair comes at the cost of tissue contracture due to the inability of the myofibroblast to regenerate tissue. When contracture and ECM remodeling become progressive and manifest as organ fibrosis, stiff scar tissue obstructs and ultimately destroys organ function. In addition to being a consequence of myofibroblast activities, the mechanical properties of scarred fibrotic organs promote myofibroblast contraction and differentiation. I will give a brief overview on how mechanical factors control development of myofibroblasts and fibrosis.

One essential element in this detrimental feed forward loop of myofibroblast contraction and ECM stiffening is the mechanical activation of the pro-fibrotic growth factor TGF-β1 from stores in the ECM. Our previous research demonstrated a mechanical pulling mechanism of TGF-β1 activation, requiring integrins, cell contraction, and binding of the latent TGF-β1 binding protein-1 (LTBP-1) to a stiff ECM. We now tested whether the organization level of LTBP-1 controls the availability of TGF-β1 for mechanical activation by pre-straining the latent complex, analogous to loading a mechanical spring. Our results show that myofibroblasts organize fibrillar structures from LTBP-1 that is 1) endogenously produced, 2) offered as non-organized ECM produced by different cell-expression systems, and 3) added soluble to the culture medium of myofibroblasts. The percentage of contraction-activated TGF-β1 of total TGF-β1 correlated with the organization degree of LTBP-1 ECM in all conditions. Moreover, pre-straining cell free LTBP-1 ECM using a mechanical strain device enhanced activation of TGF-β1 by myofibroblast contraction compared with relaxed LTBP-1 ECM. We conclude that myofibroblasts remodel LTBP-1 into strained fibrillar structures. The organization level/pre-strain of the TGF-β1 complex will determine the amount of active TGF-β1 released from the ECM by myofibroblast contraction.

Chairperson: Donald Gullberg, CCBIO