Blood vessels via reprogramming of peripheral blood cells

Blood vessels via reprogramming of peripheral blood cells: Human peripheral blood mononuclear cell-derived induced pluripotent stem cells for the in vitro fabrication of autologous endothelialized bioengineered large diameter vascular grafts Todays vascular replacement materials are associated with several limitations, including thrombogenicity, calcific degeneration and lack of growth. In particular in patients suffering from congenital heart disease improved cardiovascular replacement materials are most needed. Therefore, the use of growing vascular replacement constructs made of autologous cells would significantly reduce todays therapeutic limitations, which are mainly due to the need for repeated re-interventions given the significant size mismatch during somatic growth. The Weber group and others have shown the feasibility to engineer functional bioengineered blood vessels or heart valves in vitro based on autologous cell systems and rapidly degrading polymer materials. However, in spite of the promising experimental results, no clinical trials based on the in vitro tissue engineering approach have been initiated so far due to the lack of an appropriate cell source. Initially, mature vascular-derived cells have been isolated from the vena saphena of patients, which requires the harvest of intact donor tissue. In the attempt of establishing less invasive cell sources, mesenchymal stem cells (MSCs) have been isolated from fetal tissues, adipose tissue or bone marrow. In a series of studies the feasibility of using MSCs for the vascular tissue engineering approach has been demonstrated. However, also these cells are associated with significant limitations: Fetal adnexal tissues are limited to prenatally diagnosed defects only and postnatal MSCs also require an additional surgical intervention. In addition, MSCs have been used to generate the interstitial component of vascular constructs, however, derivation of endothelial cells from these sources in sufficient quantities seems difficult. In the contrary, peripheral blood-dervived monoculear cells (PBMCs) would represent an ideal cell source for vascular tissue engineering as they are easily and repeatedly accessible in large numbers. However, direct isolation of all vascular cell phenotypes in sufficient amounts required for tissue engineering from peripheral blood hasnt been feasible so far. The recently emerged technology of induced pluripotent stem cells (iPSCs) may have the potential to overcome this hurdle as they would allow for the generation of autologous patient-specific cells with a desired (vascular) phenotype. Therefore, the presented project aims at generating tissue engineered vascular replacement constructs from vascular cells that were differentiated out of PBMC-derived iPSCs. After culturing the constructs under dynamic flow and pressure conditions, we will evaluate their biomechanical properties as well as the extracellular matrix composition and compare them with constructs generated from vascular control cells. Finally, the engineered constructs will be evaluated in a murine animal model to confirm in vivo functionality of the engineered tissues. This approach would allow for using peripheral blood as a single autologous cell source for in vitro engineering of large diameter vascular grafts in the future.