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 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 determined. They are generally presumed to originate from the donor media, 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 (refs. 8,9). Moreover, subpopulations of bone-marrow and circulating cells can differentiate into endothelium, and implanted synthetic vascular grafts are seeded by host SMCs and endothelium. Here we used murine aortic transplants to formally identify the source of SMCs in GAD lesions. Allografts in beta-galactosidase transgenic recipients showed that intimal SMCs derived almost exclusively from host cells. Bone-marrow transplantation of beta-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.

In Vivo Characterization of Bone Marrow–Derived Fibroblasts Recruited into Fibrotic Lesions

“…For reprints contact: Reprints@AlphaMedPress.com 700 Bone Marrow-Derived Fibroblasts Recruited into Fibrotic Lesions transplantation of bone marrow (BM), hematopoietic stem cells or nonhematopoietic mesenchymal stem cells, muscle [7][8][9][10][11], heart [12][13][14], liver [15][16][17][18][19], vascular cells [20,21], and other mesenchymal cells [22][23][24] of donor origin have been detected. Investigators revealed that BM-derived cells can be progenitors for tissue fibroblasts that are recruited through the circulation to populate peripheral organs [25][26][27][28][29].…”

The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

“…Adventitial fibroblasts may also migrate to the intima, differentiate into myofibroblasts and contribute to neointima formation (27,28). Moreover, several groups have shown that bone marrow-derived vascular cells with some characteristics of VSMCs accumulate in the neointima of transplant vasculopathy and in a severe vascular injury animal model (29)(30)(31). Cell division involves two consecutive processes: interphase, ie, the time between two mitosis (M) periods, and the mitosis itself, ie, the process of cell division.…”

Hematopoietic Stem Cells Contribute to the Regeneration of Renal Tubules after Renal Ischemia-Reperfusion Injury in Mice

“…The pluripotency of HSC is evidenced by their capacity to differentiate into multiple lineages within the blood and immune system, as well as cells of non-hematopoietic tissues, such as hepatocytes, cardiac myocytes, gastrointestinal epithelial cells, and vascular endothelial cells (7)(8)(9)(10)(11). The discovery that adult HSC can cross lineage boundaries to become cells of other tissues has challenged the traditional view that somatic stem cells are lineage-restricted and organ-specific (12).…”