Synthetic Mesenchymal Stem Cell Niches for Vascular Therapy

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Hemodialysis vascular access dysfunction is currently considered to be one of the most challenging forms of clinical vascular grafting. The high failure rates associated with all types of dialysis vascular access that include arteriovenous fistulae (AVFs) and arteriovenous grafts (AVGs), lead to substantial morbidity, mortality, and economic cost. No effective solutions exist. End-stage renal disease and other health conditions of hemodialysis patients present a hostile environment that includes uremic toxins and inflammatory cytokines. The maturation failure of AVFs and AVGs is related to unresponsive or dysfunctional vascular cells, which can be attributed in part to this hostile milieu in the blood and in part to the dysfunctional matrix that alters the local strains during blood flow. For AVFs and AVGs to be successful, they must maintain a healthy vascular cell phenotype despite these hostile conditions. The central hypothesis for the parent project (5R01HL119371) is that precision cell niches, developed under hemodialysis-relevant conditions and when applied to the clinical setting of dialysis vascular access, prevent dialysis access failure. The goal for this supplement award is to create a physiologically- relevant three-dimensional (3D) model of the media layer of a blood vessel that would allow for a more accurate study of vascular smooth muscle cells (vSMCs) in vitro. The key attributes of the model will be a 3D media- mimetic that recapitulates: (1) the extracellular matrix (ECM) of the native media layer and (2) the complex strain environment that arises during pulsatile blood flow. The model will be based on an innovative embedded fiber hydrogel model developed by the team, but which will be adapted to recapitulate the native 3D environment of vSMCs. The hydrogel model will consist of a fiber (that mimics the ECM of the intima) seeded with vSMCs and embedded within a bulk hydrogel matrix comprised of matrix metalloproteinase-sensitive crosslinks and cell adhesion peptides that mimic the media layer. Importantly, the structural design of the model allows for control over the integration bond between the intima-like fiber and the media matrix to determine how much strain is transferred to the cells. This bond allows for the local strain to be varied (e.g., pathophysiological to normal) without altering the properties of the fiber or hydrogel matrix. By creating a more physiologically accurate model of the media layer, the information gained from in vitro studies should better translate to in vivo studies. This project will test the overarching hypothesis that abnormally high tensile strains contribute to a pathological phenotype in vSMCs, which is exacerbated under uremic conditions, but a cell protective and regenerative signal released from the fibers prevents a dysfunctional vSMC phenotype. To test this hypothesis two specific aims are proposed. AIM 1 will determine the effect of local strains on vSMC phenotype under uremic conditions. AIM 2 will assess the effect of antioxidants (i.e., hydrogen sulfide) on preserving the vSMC phenotype under uremic conditions. Taken together, this project will provide deeper insights into the synergistic effect of tensie strain and the hostile milieu on vSMC dysfunction through a novel 3D media-mimetic hydrogel model.