Origin of mesenchymal FAP+ cells and their function as regulators of body size
Stromal cells expressing fibroblast activation protein alpha (FAP) regulate homeostasis in multiple tissues, including bone, muscle and adipose. However, the source of these cells, and their roles in regulating body growth and size, remain unexplored. In this study we show that FAP+ cells accumulate in tissues during juvenile growth through proliferation, which ceases in adult animals. Moreover, depletion of FAP-expressing cells in growing animals results in irreversible reduction in total body size, revealing non-redundant role of those cells in growth. Interestingly, FAP+ stromal cells from various tissues are transcriptionally highly similar, suggesting that they form a unique stromal lineage. Using a novel transgenic mouse in which indelible marking of FAP-expressing cells can be controlled by administration of doxycycline, we show that adult mesenchymal cells, including adipocytes, muscle fibres, articular chondrocytes and osteoblasts, originate from embryonic FAP+ precursors. Finally, restriction of an activating mutation in PI3K to postnatal FAP+ cells is sufficient to trigger skeletal overgrowth and results in greater total body size. Altogether these findings emphasise the role of FAP+ cells in regulation of growth and the determination of body size.