Long-term solid-organ allografts typically develop diffuse arterial intimal lesions (graft arterial disease;
GAD), consisting of smooth-muscle cells (SMC), extracellular matrix and admixed mononuclear leukocytes. GAD
eventually culminates in vascular stenosis and ischemic graft failure. Although the exact mechanisms are
unknown, chronic low-level alloresponses likely induce inflammatory cells and/or dysfunctional vascular wall
cells to secrete growth factors that promote SMC intimal recruitment, proliferation and matrix synthesis.
Although prior work demonstrated that the endothelium and medial SMCs lining GAD lesions in cardiac
allografts are donor-derived, the intimal SMC origin could not be determined4. They are generally presumed
to originate from the donor media5, leading to interventions that target donor medial SMC proliferation,
with limited efficacy. However, other reports indicate that allograft vessels may contain host-derived
endothelium and SMCs. Moreover, subpopulations of bone-marrow and circulating cells can differentiate into
endothelium, and implanted synthetic vascular grafts are seeded by host SMCs and endothelium12,13. Here we
used murine aortic transplants to formally identify the source of SMCs in GAD lesions. Allografts in
ß-galactosidase transgenic recipients showed that intimal SMCs derived almost exclusively from host cells.
Bone-marrow transplantation of ß- galactosidase–expressing cells into aortic allograft recipients
demonstrated that intimal cells included those of marrow origin. Thus, smooth-muscle–like cells in GAD
lesions can originate from circulating bone-marrow–derived precursors.
Host Bone-marrow Cells are a Source of Donor Intimal Smooth-muscle–like Cells in Murine Aortic Transplant Arteriopathy
Koichi Shimizu, Seigo Sugiyama, Masanori Aikawa, Yoshihiro Fukumoto, Elena Rabkin, Peter Libby & Richard N. Mitchell
Nature Medicine • Volume 7 • Number 6 • Pages 738-741 • June 2001