Abstract 3950: Bone Marrow Progenitor Cells Repair the Endothelium Overlying Sites of Damaged Smooth Muscle Cells in the Ascending Aorta in a Mouse Model of Progeria
Hutchinson-Gilford Progeria is an autosomal dominant syndrome resulting in early death in childhood due to cardiovascular events. Transgenic mice were generated using a bacterial artificial chromosome (BAC), engineered to carry the common G608G mutation of the human lamin A gene coding for the dysfunctional protein, progerin, that is responsible for this progeria syndrome in children. We consistently observed that the elastic lamellae in the media in BAC+ mice appeared to be intact and that interlamellar spaces in the ascending aorta were occupied by a few widely scattered smooth muscle cells surrounded by extensive extracellular matrix resulting in an increase in media thickness. MRI and echocardiography measurements of the ascending aorta showed smaller dimensions in BAC+ mice (n=8) versus wild type (n=4) (p<0.009). In an effort to correct these defects we transplanted 25x10e6 nucleated bone marrow (BMT) cells from healthy EGFP+ donors into 6 –7 day old neonatal BAC+ mice and achieved greater than 90% chimerism in circulating blood cells. Twelve months following BMT, confocal microscopy revealed endothelial cell replacement by donor-derived EGFP+ cells overlying damaged media, but no EGFP+ cells were found in the media. Wherever endothelial cell replacement was observed, the adventitial layer displayed numerous EGFP+ cells. In contrast, the healthy regions of the aorta, including the entire descending aorta, lacked EGFP+ cells in the endothelium and media, with few present in adventitia. There was no evidence of improved dimensions of the ascending aorta of BAC+ mice (n=4) following BMT compared with BAC+ non-BMT mice (p=0.8). We conclude that BM-derived progenitor cells homed to and regenerated endothelium in the structurally and functionally abnormal ascending aorta of BAC+ mice, likely due to shear stress-induced injury. Importantly, they did not repair the smooth muscle defect, nor did they participate in the turnover of normal endothelium or smooth muscle in the intact aorta.