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Host bone-marrow cells are a source of donor intimal smooth- muscle–like cells in murine aortic transplant arteriopathy

Abstract

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 synthesis1,2,3. 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 efficacy6,7. However, other reports indicate that allograft vessels may contain host-derived endothelium and SMCs (refs. 8,9). Moreover, subpopulations of bone-marrow and circulating cells can differentiate into endothelium10,11, 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 β-galactosidase transgenic recipients showed that intimal SMCs derived almost exclusively from host cells. Bone-marrow transplantation of β-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.

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Acknowledgements

This study was supported in part by National Institutes of Health Grant RO1 HL-43364. We thank K. Takayama, E. Shvartz, C.C. Hill, E. Simon-Morrissey, M. Muszynski, I. Chulsky, T. Shimizu and S. Cole for their technical expertise; K.E. Williams for her editorial assistance; A. Lichtman for his helpful comments; and D.G. Farley and his staff at the mouse facility of Brigham and Women's Hospital and Harvard Medical School for their excellent management of experimental mice.

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Correspondence to Richard N. Mitchell.

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Figure 1: Characterization of the cell populations in aortic allograft intima.
Figure 2: Intimal SM-like cells in the allograft intima are of recipient origin.
Figure 3: Bone-marrow origin of SM-like cells in allograft intima. Blue color shows X-gal staining (β-gal activity).