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Lipogenesis is an ancestral mechanism used in mammalian cartilage morphogenesis

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Cartilages are a diverse group of tissues that form an essential component of the skeletal system. Cartilage-forming cells, aka chondrocytes, form cartilage by secreting a diverse array of structural molecules into the extracellular matrix (ECM), including multiple collagens and proteoglycans, conferring the tissue with shock-absorbing and/or elastic properties. In addition to its impact-buffering role in the axial and appendicular skeleton, cartilage plays an important part in the development and proper function of the skull, and many key regulators of chondrocyte specification and development in the head have been found. Conversely, the biology of many adult secondary or accessory cartilages such as those of the external ear or nasal capsule is still understudied. In this work, we show that, in mice, multiple head and neck cartilages, including neural crest-derived ear, nasal, thyroid, and epiglottic cartilages are composed of lipid-laden cartilage cells called lipochondrocytes. Initially identified by famed anatomist Franz von Leydig in the 1850s, lipochondrocytes were the subject of a series of studies in the 1960s and 1970s only to fall back into obscurity, and are still undescribed in modern studies.

Morphologically, lipochondrocytes resemble white adipocytes, but have distinct lipidomic and transcriptomic profiles. Importantly, lipochondrocytes lack many key components of lipid uptake and mobilization pathways, including many fatty acid transporters and lipolytic enzymes. Unlike adipocytes, the lipid droplets in ear lipochondrocytes are insensitive to metabolic stressors, namely obesity and caloric restriction. In ear cartilage, lipid droplet synthesis primarily depends on de novo lipogenesis, and its pharmacological or genetic inhibition disrupts proper cartilage formation, leading to mice having smaller and misshapen ears.

Further, we observed lipochondrocytes in several facial cartilages of multiple mammalian species, including in bats, primates, carnivores and even marsupials suggesting that a lipochondrocyte-like cell could have existed in the common ancestor of all extant therians. In this thesis, I bring the lipochondrocyte back into view using modern methods in molecular biology, and open new research avenues in the fields of cellular, developmental, and evolutionary biology.

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This item is under embargo until December 4, 2023.