Characterizing On‐Chip Angiogenesis Induction in a Microphysiological System as a Functional Measure of Mesenchymal Stromal Cell Bioactivity

Abstract

Mesenchymal stromal cells (MSCs) continue to be proposed for clinical investigation to treat myriad diseases given their purported potential to stimulate endogenous regenerative processes, such as angiogenesis. However, MSC functional heterogeneity has hindered clinical success and still poses a substantial manufacturing challenge from a product quality control perspective. Here, a quantitative bioassay based on an enhanced‐throughput is described, microphysiological system (MPS) to measure the specific bioactivity of MSCs to stimulate angiogenesis as a potential measure of MSC potency. Using this novel bioassay, MSCs derived from multiple donors at different passages are co‐cultured with human umbilical vein endothelial cells and exhibit significant heterogeneity in angiogenic potency between donors and cell passage. Depending on donor source and cellular passage number, MSCs varied in their ability to stimulate tip cell dominant or stalk cell dominant phenotypes in angiogenic sprout morphology which correlated with expression levels of hepatocyte growth factor (HGF). These findings suggest that MSC angiogenic bioactivity may be considered as a possible potency attribute in MSC quality control strategies. Development of a reliable and functionally relevant potency assay for measuring clinically relevant potency attributes of MSCs will help to improve consistency in quality and thereby, accelerate clinical development of these cell‐based products.

Vascular microphysiological systems

“…Some are working to make vascular MPS more scalable and robust [13], while others have leveraged the ability to perform multicellular functional assays for quality control of cell products. For example, a group at the FDA described using a microfluidic model to assess the ability of mesenchymal stem cells (MSC) to induce angiogenesis and vasculogenesis, potentially predicting their ability to contribute to wound healing and re-vascularization in vivo [14 ▪ ]. The authors were also able to use this data to identify factors which they described as either ‘sprouting’ or ‘lumenizing’ based on correlating real-time quantitative polymerase chain reaction (RT-qPCR) data with image analysis.…”