A Dense Fibrillar Collagen Scaffold Differentially Modulates Secretory Function of iPSC-Derived Vascular Smooth Muscle Cells to Promote Wound Healing

The application of human-induced pluripotent stem cells (hiPSCs) to generate vascular smooth muscle cells (hiPSC-VSMCs) in abundance is a promising strategy for vascular regeneration. While hiPSC-VSMCs have already been utilized for tissue-engineered vascular grafts and disease modeling, there is a lack of investigations exploring their therapeutic secretory factors. The objective of this manuscript was to understand how the biophysical property of a collagen-based scaffold dictates changes in the secretory function of hiPSC-VSMCs while developing hiPSC-VSMC-based therapy for durable regenerative wound healing. We investigated the effect of collagen fibrillar density (CFD) on hiPSC-VSMC’s paracrine secretion and cytokines via the construction of varying density of collagen scaffolds. Our study demonstrated that CFD is a key scaffold property that modulates the secretory function of hiPSC-VSMCs. This study lays the foundation for developing collagen-based scaffold materials for the delivery of hiPSC-VSMCs to promote regenerative healing through guiding paracrine signaling pathways

Artery to vein configuration of arteriovenous fistula improves hemodynamics to increase maturation and patency

International audienceArteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, but 60% of conventional [vein-to-artery (V-A)] AVF fail to mature, and only 50% remain patent at 1 year. We previously showed improved maturation and patency in a pilot study of the radial artery deviation and reimplantation (RADAR) technique that uses an artery-to-vein (A-V) configuration. Here, we show that RADAR exhibits higher rates of maturation, as well as increased primary and secondary long-term patencies. RADAR is also protective in female patients, where it is associated with decreased reintervention rates and improved secondary patency. RADAR and conventional geometries were compared further in a rat bilateral carotid artery-internal jugular vein fistula model. There was decreased cell proliferation and neointimal hyperplasia in the A-V configuration in male and female animals, but no difference in hypoxia between the A-V and V-A configurations. Similar trends were seen in uremic male rats. The A-V configuration also associated with increased peak systolic velocity and expression of Kruppel-like factor 2 and phosphorylated endothelial nitric oxide synthase, consistent with improved hemodynamics. Computed tomography and ultrasound-informed computational modeling showed different hemodynamics in the A-V and V-A configurations, and improving the hemodynamics in the V-A configuration was protective against neointimal hyperplasia. These findings collectively demonstrate that RADAR is a durable surgical option for patients requiring radial-cephalic AVF for hemodialysis access

The potential and limitations of induced pluripotent stem cells to achieve wound healing

Abstract Wound healing is the physiologic response to a disruption in normal skin architecture and requires both spatial and temporal coordination of multiple cell types and cytokines. This complex process is prone to dysregulation secondary to local and systemic factors such as ischemia and diabetes that frequently lead to chronic wounds. Chronic wounds such as diabetic foot ulcers are epidemic with great cost to the healthcare system as they heal poorly and recur frequently, creating an urgent need for new and advanced therapies. Stem cell therapy is emerging as a potential treatment for chronic wounds, and adult-derived stem cells are currently employed in several commercially available products; however, stem cell therapy is limited by the need for invasive harvesting techniques, immunogenicity, and limited cell survival in vivo. Induced pluripotent stem cells (iPSC) are an exciting cell type with enhanced therapeutic and translational potential. iPSC are derived from adult cells by in vitro induction of pluripotency, obviating the ethical dilemmas surrounding the use of embryonic stem cells; they are harvested non-invasively and can be transplanted autologously, reducing immune rejection; and iPSC are the only cell type capable of being differentiated into all of the cell types in healthy skin. This review focuses on the use of iPSC in animal models of wound healing including limb ischemia, as well as their limitations and methods aimed at improving iPSC safety profile in an effort to hasten translation to human studies