Thyroid eye disease (TED) is the most common orbital disease in adults. Targeting expanded orbital adipose tissue (OAT) removed by surgery has therapeutic potential. However, drugs targeting OAT are unavailable because of the lack of deciphering features of OAT. Here, we aimed to investigate the mechanism underlying OAT expansion and identify a drug targeting OAT in TED. We found an increasing number of adipocytes with smaller size in TED-derived OATs as compared with controls, indicating that hyperplasia rather than hypertrophy contributed to OAT enlargement in TED. Typically smaller-sized adipocytes in TED patient-derived OATs were noted to localize surrounding vessels. RNA sequencing revealed enriched vascular endothelial growth factor receptor (VEGFR) genes in adipocytes differentiated from preadipocytes of TED-derived stromal vascular fraction (SVF). Similarly, OATs in patients with TED also expressed a higher level of VEGFR-1 and -2. We induced adipogenesis in TED-derived SVF with or without Lenvatinib, an FDA-approved small-molecule VEGFR inhibitor. Lenvatinib significantly suppressed lipid accumulation in a dose-dependent manner. In conclusion, our study revealed the potential anti-adipogenic effect of Lenvatinib on the OAT of TED-affected patients. In addition to proposing a drug for TED treatment, this study shows the therapeutic potential of anti-adipogenesis drugs targeting the VEGF pathway.

Cerebrospinal fluid (CSF) surrounding the optic nerve is essential for nutrient transport, waste removal, and optic nerve function. Optic disc edema in astronauts during long-duration spaceflight-Spaceflight Associated Neuro-Ocular Syndrome (SANS)-may result from impaired optic nerve CSF drainage, but the drainage pathway remains unclear. Given that the optic nerve sheath is an extension of the cranial meninges, we hypothesized that its CSF drains via lymphatic vessels rather than refluxing into the cranium. We assessed the pressure relationship between intracranial and optic nerve CSF and traced its drainage pathway. Our results show that optic nerve sheath CSF pressure is consistently lower than intracranial pressure, with no reflux observed. Instead, optic nerve CSF drains into deep cervical lymph nodes via lymphatic vessels within the sheath. These findings provide new insights into optic nerve CSF dynamics and may help elucidate SANS pathogenesis.

The cerebrospinal fluid (CSF) surrounding the optic nerve (to differentiate with the intracranial CSF, it is named as optic nerve CSF) plays important roles in nutrient exchange, waste removal, and maintenance of optic nerve function. Recent studies have suggested that the optic disc edema observed in astronauts may be linked to the retention of CSF around the optic nerve, and this retention may even be derived from impaired drainage of optic nerve CSF. However, how the optic nerve CSF is drained out remains inconclusive. We speculated that the optic nerve CSF may be drained out through lymphatic vessels of the optic nerve sheath. Here, we found by immunofluorescence and in vivo fluorescence imaging that, in both rats and humans, the optic nerve sheath has lymphatic vessels. Furthermore, we observed that the pressure in the optic nerve CSF is lower than the intracranial pressure, and the optic nerve CSF does not reflux into the intracranial space but is, instead, drained out into the deep cervical lymph nodes (dcLNs) through the lymphatic vessels in the optic nerve sheath. These observations have significant implications for understanding the physiological turnover and drainage pathways of optic nerve CSF. It may also help better understand the pathogenesis underlying spaceflight and Spaceflight Associated Neuro-Ocular Syndrome (SANS).