Fibro-Adipogenic Progenitors From Skeletal Muscle Enhance Microvascular Angiogenesis in a 3D Model

Skeletal muscle tissue is highly vascularized, and angiogenesis plays a key role in both muscle homeostasis and regeneration. Despite their importance in regulating various processes within skeletal muscle, little is known about the role of muscle-resident fibro-adipogenic progenitors (FAPs) in promoting microvascular angiogenesis. In order to better understand the effects of FAPs on angiogenesis, FAPs were co-cultured with adipose-derived microvascular fragments (MVFs) in three-dimensional fibrin hydrogels. We further tested if pre-culturing FAPs in brown adipogenic induction media (BAM) influences their ability to promote MVF angiogenesis. MVFs co-cultured with control FAPs or BAM FAPs for 5 days exhibit robust microvascular network formation with significantly increased vessel percentage area and average vessel length compared to MVFs alone. FAPs cultured in BAM prior to co-culture with MVFs alter vascular network development compared to MVFs co-cultured with control FAPs by significantly increasing average vessel length. Collectively, these results indicate that FAPs are key regulators of microvascular angiogenesis and that BAM FAPs have an improved capacity to promote increases in average vessel length. The current findings support the transplantation of FAPs and MVFs and modulation of FAP pro-angiogenic properties as potential therapeutic approaches for enhancing skeletal muscle angiogenesis in the context of injury and disease.