Facilitating islet implantation and engraftment following transplantation using primed umbilical cord mesenchymal stem therapies and focused ultrasound

About This Grant

PROJECT SUMMARY In both autologous and allogenic islet transplantation, islets need to pass through the following steps: Step 1 - Isolation: When islets are extracted from the pancreas, they are subject to chemical and physical digestion steps that places them under significant stress, leaving them in a “fragile state” with metabolic dysfunction that makes them highly susceptible to any further injury. Step 2 - Implantation: When delivered into the liver via infusion into the portal vein, islets encounter a relatively hostile microenvironment which is hypoxic and contains high concentrations of metabolites, as well as being subject to an instant blood-mediated inflammatory reaction (IBMIR) that involves activation of the complement and coagulation cascades. Step 3 - Engraftment: Once islets settle within hepatic sinusoids, they need to remodel the extracellular matrix (ECM) and form new connections with the host tissue as well as develop a new vascular supply from branches of the hepatic artery to meet their ongoing metabolic demands. Unfortunately, these processes collectively place significant stress on islets, resulting in almost 60% of them being lost within the first 2-3 weeks following transplantation. One promising approach to help rescue and protect islets through these steps is to use mesenchymal stem/stromal cells (MSCs). Our data supports the use of umbilical cord derived MSCs (UC-MSCs) as an optimal candidate for islet transplantation, given they can be easily derived and expanded, are relatively homogenous across donors, and have an enhanced anti-inflammatory and immunomodulatory capacity. However, they unfortunately express tissue factor (TF) which will reduce their ability to be used with islets when administered into the portal vein given this will exacerbate the IBMIR. Recently, we developed a novel approach using pulsed focused ultrasound (pFUS) to reproducibly prime UC-MSCs (pUC-MSCs), resulting in them having an enhanced bioenergetic capacity, reduced expression of TF and enhanced expression of ECM remodeling and angiogenic factors. Interestingly pFUS also increases the synthesis and secretion of extracellular vesicles (pUC-EVs; a novel and clinically scalable cell-free therapy), with these vesicles also demonstrating a reduced ability for activating the coagulation cascade. We have also demonstrated the ability of pFUS to stimulate islet function and viability, in addition to priming sites of islet transplantation where sonicated tissue resulted in improved islet engraftment. Hence, in this proposal, we aim to validate these clinically scalable therapies (i.e. pUC-MSCs and pUC-EVs from different human donors to ensure reproducibility) and our novel technology (i.e. pFUS for islet and organ priming) to improve the functionality of isolated islets (Aim 1 – addressing Step 1), their survival following implantation into the liver (Aim 2 – addressing Step 2), and their subsequent engraftment (Aim 3 – addressing Step 3). Finally, we will also examine if pUC-MSCs and pUC-EVs can rescue islet function post transplantation, especially when given directly into the liver via locoregional delivery into the hepatic artery.