WORCESTER POLYTECHNIC INSTITUTE
Recent evidence suggests that the delivery of human mesenchymal stem cells (hMSCs) to the infarcted heart improves mechanical function in both clinical and experimental animal studies, although the functional mechanism remains equivocal. A major limitation of cell delivery systems for cardiac repair has been ineffective localization, persistence and retention of physiologically relevant numbers of cells in the heart. Recently, our laboratories have developed a new method of producing biopolymer microthreads that can be tailored to modulate cell attachment and migration. In addition, we have developed a novel method to induce hMSCs to express cardiac specific markers. We will use our novel microthread technology to deliver hMSCs that express cardiac specific markers to determine if we can increase regional mechanical function in the infarcted heart.
In our first specific aim, we will maximize cell loading onto biopolymer microthreads for delivery to the heart. We hypothesize that hMSCs seeded on biopolymer microthreads will enhance targeted cell delivery to the myocardium. Quantum dot loaded hMSCs will be incubated on fibrin microthreads. Following a period of attachment and growth on fibrin microthreads, hMSC stemness, morphology, cell density, and survival will be assessed to characterize cell quantity and phenotype in microthread delivery systems. Concurrently, we will determine the mechanical strength of these cell-seeded microthreads to assess their stability for implantation in the heart. Finally, these cell-seeded microthreads will be deployed into the beating rat heart. Cell engraftment will be assessed at 0 and 3 days post implantation.
In our second specific aim, we will assess the effects of microthread-mediated hMSC delivery on left ventricular function in the infarcted rat heart in vivo. We hypothesize that microthread-mediated hMSC delivery will improve hMSC engraftment and resultant regional function in the infarcted rat heart. Cell-seeded microthreads will be delivered to the infarcted myocardium so that they span the region of the infarct and the peri-infarct border. Regional mechanical function will be assessed, along with histological evaluation of hMSC localization, survival, proliferation, engraftment, and differentiation within the infarcted heart.
This microthread-based delivery system will provide effective localization of stem cells to the heart. This method will also allow scaffold-based targeted delivery, resulting in concise placement of stem cells in the region of interest. Thus, these cell-seeded microthreads serve as a platform technology for efficiently delivering viable cells to infarcted myocardium and for precisely directing cellular function.
This administrative supplement will provide funds to determine if hMSCs committed to a cardiac linage that are delivered with our novel delivery method can improve regional mechanical function in the infarcted rat heart.