Derivation of functional vascular smooth muscle cells (VSMCs) from human induced pluripotent stem cells (hiPSCs) to generate tissue-engineered blood vessels (TEBVs) holds great potential in treating patients with vascular diseases. Herein, hiPSCs were differentiated into alpha-smooth muscle actin (α-SMA) and calponin-positive VSMCs, which were seeded onto polymer scaffolds in bioreactors for vascular tissue growth. A functional TEBV with abundant collagenous matrix and sound mechanics resulted, which contained cells largely positive for α-SMA and smooth muscle myosin heavy chain (SM-MHC). Moreover, when hiPSC-derived TEBV segments were implanted into nude rats as abdominal aorta interposition grafts, they remained unruptured and patent with active vascular remodeling, and showed no evidence of teratoma formation during a 2-week proof-of-principle study. Our studies represent the development of the first implantable TEBVs based on hiPSCs, and pave the way for developing autologous or allogeneic grafts for clinical use in patients with vascular disease.

A. The mouse aortocaval fistula recapitulates human arteriovenous fistula maturation. Am J Physiol Heart Circ Physiol 305: H1718 -H1725, 2013. First published October 4, 2013 doi:10.1152/ajpheart.00590.2013.-Several models of arteriovenous fistula (AVF) have excellent patency and help in understanding the mechanisms of venous adaptation to the arterial environment. However, these models fail to exhibit either maturation failure or fail to develop stenoses, both of which are critical modes of AVF failure in human patients. We used high-resolution Doppler ultrasound to serially follow mice with AVFs created by direct 25-gauge needle puncture. By day 21, 75% of AVFs dilate, thicken, and increase flow, i.e., mature, and 25% fail due to immediate thrombosis or maturation failure. Mature AVF thicken due to increased amounts of smooth muscle cells. By day 42, 67% of mature AVFs remain patent, but 33% of AVFs fail due to perianastomotic thickening. These results show that the mouse aortocaval model has an easily detectable maturation phase in the first 21 days followed by a potential failure phase in the subsequent 21 days. This model is the first animal model of AVF to show a course that recapitulates aspects of human AVF maturation. aortocaval fistula; arteriovenous fistula; maturation; mouse; model THE ARTERIOVENOUS FISTULA (AVF) is the most common access chosen for hemodialysis as the first-line therapy before renal replacement. Despite the superiority of AVF access compared with its alternatives, AVFs are still far from perfect. AVFs fail to "mature," e.g., dilate, thicken, and increase flow, before the beginning of dialysis in ϳ20 -50% of cases, with the majority of AVFs requiring some additional therapeutic intervention to mature successfully (9,14,20,21). In addition, 1-yr primary AVF patency rates are typically only 60 -65%, with many mature AVFs subsequently failing secondarily due to neointimal hyperplasia, generally perianastomotic (2,4,7,19,21,22). The poor patency of AVFs clearly reflects our imperfect understanding of the biology of venous remodeling to the arterial environment.The AVF has been studied using several models, including the surgical anastomosis model as well as the puncture model (1, 5, 6, 8, 10 -12, 15-17). All of these models have strengths and weakness, including technical difficulty due to surgery as well as the use of animals larger than mice (1,5,8,12,15,16). A common feature of all these models is that they are good models of surgical access, with good patency; unfortunately, they fail to exhibit a percentage of animals that either fail to mature or fail to develop stenoses in long-term followup, both of which are both important aspects of understanding modes of failure of human AVF.Recent advances in ultrasound technology have allowed increasingly accurate analysis of blood flow within small vessels, such as in a mouse, as well as allowing the ability to serially examine the same mouse over time. We used this technology to observe the time course of venous remodeling in the mouse ao...

Veins are exposed to the arterial environment during two common surgical procedures, creation of vein grafts and arteriovenous fistulae (AVF). In both cases veins adapt to the arterial environment that is characterized by different hemodynamic conditions and increased oxygen tension compared to the venous environment. Successful venous adaptation to the arterial environment is critical for long term success of the vein graft or AVF, and in both cases is generally characterized by venous dilation and wall thickening. However, AVF are exposed to a high flow, high shear stress, low pressure arterial environment, and adapt mainly via outward dilation with less intimal thickening. Vein grafts are exposed to a moderate flow, moderate shear stress, high pressure arterial environment, and adapt mainly via increased wall thickening with less outward dilation. We review the data that describe these differences, as well as the underlying molecular mechanisms that mediate these processes. Despite extensive research, there are few differences in the molecular pathways that regulate cell proliferation and migration or matrix synthesis, secretion, or degradation currently identified between vein graft adaptation and AVF maturation that account for the different types of venous adaptation to arterial environments.