Bioengineering Approach for Advancing Reparative Medicine Stem Cell Technologies

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Project Summary The goal of this proposal is to develop a model technology that enables pre-clinical investigation of adipose derived stromal vascular fraction (SVF) in a real perfused microvascular network environment over the time course of a few days. Such a model does not exist. SVF transplantation is a promising new therapy for applications spanning from cardiac ischemia to tissue repair based on the idea that SVF can form new vessels. Big knowledge gaps remain relating to the time course of the de novo vessel growth (i.e. neovascularization), the integration of SVF derived vessels with nearby microvascular networks, and the cell makeup of the new vessels. Understanding where and how SVF cells contribute to microvascular growth will help guide their therapeutic use. The PI's laboratory has developed and validated the physiological relevance of a novel rat tissue culture model that enables real-time ex vivo observation of cell dynamics in intact adult microvascular networks. This biomimetic “view” has led to discoveries related to endothelial cell dynamics and lymphatic/blood vessel plasticity. The PI's laboratory has also developed a bioreactor for introducing perfusion in the cultured microvascular networks and is now uniquely positioned to combine these approaches with murine tissue to develop a totally new technology for evaluating SVF fate and function (Figure 1). SVF therapies have not yet reached their potential. Our novel high-content tool will enable multi-cell/system readouts for angiogenesis, lymphangiogenesis, and vessel permeability that will define the scope of SVF impact. In line with the purpose of the NHLBI notice of special interest, the aims are development and discovery driven with the goal of generating new hypotheses. Aim 1: Model Development for Discovery of SVF Fate and Function – To combine bioreactor design with tissue culture to establish a perfused microvascular network model for evaluating SVF neovascularization. Aim 2: Impact for Hypothesis Generation Projects – To determine the impact of neuron-glial antigen 2 (NG2) inhibition on SVF neovascularization. The proposed research will offer a new “view” for the discovery of SVF dynamics and effects in a physiologically relevant microvascular milieu with readouts not possible with other models. The long-term objective of this work is to understand and evaluate potential SVF therapies. This proposal will demonstrate the value of a biomimetic platform for basic science studies focused on identifying SVF dynamics and elucidating how environmental, cellular, and specific molecular dynamics might guide SVF therapy.