Effective and efficient healing of wounds is crucial for preventing complications such as infection, delayed recovery, increased scarring, and even death of the organism. My research investigated the role of proteoglycan 4 (PRG4) in wound healing and regeneration. The research employed a multifaceted approach, utilizing a large animal model, transgenic murine models, and mammalian cell culture to elucidate the involvement of PRG4 in maintaining tissue homeostasis across various tissue types. Chapter 2 delved into the impact of recombinant human PRG4 (rhPRG4) treatment on skin wound healing, utilizing a clinically relevant porcine full-thickness skin wound model. These results demonstrated that topical application of rhPRG4 modulates molecular pathways associated with wound healing, leading to reduced fibrosis, enhanced angiogenesis, and the retention of adipocytes at the wound site. Interestingly, a transient increase in adipose tissue during the early stages of wound healing was observed. In Chapter 3, the study explored the impact of rhPRG4 on porcine adipocytes, revealing its role as a potent activator of PPARγ and an inducer of adipogenesis in vitro. This collaboration with Myo Palate Corporation investigated novel approaches for cultivating adipose tissue for cellular agriculture purposes. While rhPRG4 showed potential as an adipocyte inducer, its regulatory approval as a food-safe substance remained a hurdle for cultured meat production. The chapter also presented alternative, food-safe PPARγ agonists, which in combination with insulin, demonstrated high lipid yields for cultured adipocytes. Chapter 4 utilized lineage-tracing transgenic mouse models to explore Hic1+ mesenchymal progenitors and their connection with PRG4. Conditional deletion of Prg4 in these cells impacted tissue regeneration in both articular cartilage and bone. Mesenchymal Hic1+ progenitors, expressing PRG4, play an active role in the wound healing response, as evidenced by their presence at injury sites. Prg4-deficiency in these progenitors negatively affected endogenous PRG4 expression, leading to increased apoptosis and influencing various aspects of bone healing, including osteogenesis, bone turnover, and remodeling. This research sheds light on the intricate interplay between PRG4, tissue-resident mesenchymal progenitors, and the wound healing process, providing valuable insights for the development of targeted therapeutic interventions to enhance tissue repair and regeneration.