Shedding of proangiogenic microvesicles from hypertrophic scar myofibroblasts.

Hypertrophic scars are a common complication of burn injuries and represent a major challenge in terms of prevention and treatment. These scars are characterized by a supraphysiological vascular density and by the presence of pathological myofibroblasts (Hmyos) displaying a low apoptosis propensity. However, the nature of the association between these two hallmarks of hypertrophic scarring remains largely unexplored. Here, we show that Hmyos produce signalling entities known as microvesicles that significantly increase the three cellular processes underlying blood vessel formation: endothelial cell proliferation, migration and assembly into capillary-like structures. The release of microvesicles from Hmyos was dose-dependently induced by the serum protein α-2-macroglobulin. Using flow cytometry, we revealed the presence of the α-2-macroglobulin receptor-low-density lipoprotein receptor-related protein 1-on the surface of Hmyos. The inhibition of the binding of α-2-macroglobulin to its receptor abolished the shedding of proangiogenic microvesicles from Hmyos. These findings suggest that the production of microvesicles by Hmyos contributes to the excessive vascularization of hypertrophic scars. α-2-Macroglobulin modulates the release of these microvesicles through interaction with low-density lipoprotein receptor-related protein 1.

α-2-Macroglobulin induces the shedding of microvesicles from cutaneous wound myofibroblasts.

Microvesicles (MVs) are recognized as an important class of cell-to-cell messengers. Although the properties of MVs are increasingly documented, the mechanisms regulating MV biogenesis remain debated. Myofibroblasts are a key cellular component of wound healing and have been shown to produce MVs upon stimulation with serum. However, the mediator(s) responsible for the observed effect of serum on MV release have yet to be identified. To isolate the molecule(s) of interest, serum proteins were sequentially separated using chromatography, selective precipitation, and electrophoresis. MV production was assessed throughout the purification and after stimulation of myofibroblasts with two potent purified molecules. α-2-Macroglobulin (A2M) was thereby found to dose-dependently stimulate MV release. We confirmed the presence of the A2M receptor, low-density lipoprotein receptor-related protein-1 (LRP1), on myofibroblasts. Inhibition of LRP1 resulted in a significant decrease in MV production. Together, our results suggest that A2M positively regulates MV shedding through the activation of LRP1 on myofibroblasts.

Microvesicles: Intercellular messengers in cutaneous wound healing.

Longtime considered as inert cellular debris, microvesicles (MVs) have gained tremendous attention in the past decade. MVs are 100-1000 nm vesicles released into the extracellular environment by the outward budding and fission of the plasma membrane. They are now regarded as essential mediators of cell-to-cell interactions in a variety of physiological and pathological processes. In this review, we discuss the increasingly recognized contribution of MVs to the biology of wound healing. We highlight current concepts relating to the biogenesis and mode of action of MVs. We discuss the emerging roles of MVs in the hemostatic, inflammatory, proliferative, and remodeling phases of the injury-repair response. In doing so, we provide a new perspective on the dynamics of intercellular communication involved in skin homeostasis.