Tissue‐intrinsic circadian clock dysfunction confers transplant rejection

Abstract

To determine the role of intrinsic tissue clocks versus extrinsic clocks in peripheral tissue disease, we implemented an organ transplant approach (blood vessel grafting) to surgically assemble a chimeric mouse that was in part wild-type and in part circadian clock mutant. Aortic isografts from donor wild-type mice that had been anastamosed to common carotid arteries of recipient WT mice (WT:WT) were pulsating with blood flow and oscillating with a circadian rhythm after four weeks. Surprisingly, when wild-type grafts were anastamosed to mice with disrupted circadian clocks, the structural adaptation was comparable to WT:WT grafts. In contrast, aortic grafts from Bmal1-KO or PerCdKO mice transplanted into litter-mate control WT developed arteriosclerotic lesions, suggesting that circadian clock gene dysfunction intrinsic to peripheral tissues is necessary to confer pathological responses. These data demonstrate the significance of tissue circadian clocks as an autonomous influence in peripheral tissue disease and additionally reveal the potential influence of circadian rhythm in the therapeutic success of organ transplantation.