Abstract 491: Injury-Activated TGFβ Recruits MSCs for Vascular Remodeling

Abstract

Stem/progenitor cells can be recruited to participate in tissue remodeling, regeneration, or repair following injury. In particular, bone marrow-derived or local resident stem /progenitor cells are implicated in vascular repair and remodeling. It is believed that migratory factor(s) released by injured tissue creates a gradient to mediate the migration of stem cells to the injury sites. The key mediator(s) inducing the recruitment of the cells to the vascular lesions remains to be defined. Here we show that nestin + cells, which represent similar population as Sca1 + CD29 + CD11b - CD45 - mesenchymal/stromal stem cells (MSCs), were recruited and incorporated into the neointimal tissue in both rat model of balloon injury of carotid artery and mouse model of wire injury of femoral artery. Importantly, elevated active TGFβ1 level was observed in the injured vessels as early as 8 hr post injury, and the elevation lasted for 2 wks. To investigate whether injury-induced activation of TGFβ1 in vascular matrix stimulates migration of MSCs, we developed an aorta-conditioned medium (Aorta-CM)-based cell migration assay in which MSCs were placed in the upper chamber and the Aorta-CM prepared by culturing ex vivo injured aorta was placed in the lower chamber of a transwell chamber. Aorta-CM prepared from ex vivo injured aorta significantly enhanced cell migration compare to CM prepared from uninjured aorta. When neutralizing antibody specific for TGFβ1 or the inhibitor of TGFβ type I receptor (TβRI) was added to the CM, the migration of MSCs was almost abolished, indicating that active TGFβ1 released by the injured arteries mediates MSCs migration. To examine the role of TGFβ in MSCs recruitment following vascular injury in vivo , TβRI inhibitor was injected into mice with injury of femoral arteries. Both the development of neointima and the recruitment of nestin + cells were blocked with the inhibitor treatment compare to those with vehicle treatment. Collectively, the results suggest that TGFβ is an injury-activated messenger essential for the recruitment of MSCs to participate in vascular remodeling.