Research Group

  • Dr. Koichi Shimizu, Principal Investigator
  • Dr. Richard Mitchell, Consultant
  • Dr. Peter Libby, Consultant


  • Brigham & Women's Hospital, Boston, USA


  • Source of Intimal Smooth Muscle like Cells in Aortic Allograft Arteriopathy

Because of excellent therapeutic strategies to prevent acute allograft rejection, graft arterial disease (GAD) is now the most important long-term obstacle to successful solid organ transplantation. The arteries of allografted organs typically develop severe, diffuse intimal hyperplastic lesions leading eventually to luminal stenoses and to ischemic graft failure. These lesions consist primarily of smooth muscle cells (SMCs) and associated extracellular matrix, admixed with infiltrating mononuclear leukocytes. The intimal lesions result from an initial alloimmune response, although the exact mechanisms remain to be elucidated. The SMCs forming the intimal hyperplastic GAD are thought to originate from medial SMCs.

Although bone marrow (BM) stem cells can develop into multiple mesenchymal lineages, only recently has it been demonstrated that BM-derived circulating cells also have the specific ability to differentiate into the intimal SM-like cells in vascular grafts. To show this we performed murine aortic transplantation into irradiated recipients of β-galactosidase transgenic (ROSA26) BM cells. The aortic graft intima contained numerous SM-like cells, which also showed β-galactosidase activity. We hypothesize that GAD SM-like cells derive primarily from such circulating BM stem cells. Such a finding is a paradigm shift from the current view that these cells derive from the underlying media. Moreover, this has profound implications regarding the therapy for GAD, as well as for more typical atherosclerotic lesions.

Our objective is the identification and characterization of the cells forming the intimal hyperplastic lesions of allograft arteriopathy, and in particular their recruitment and activation requirement.

The demonstration of BM-derived intimal SM-like cells and identification of SM-like cell specific recruitment and activation will lay the groundwork for future experiments where GAD-preventive therapeutic genes or drugs may be targeted not to donor medial SMC, but rather to recipient SM-stem cells.