Piezo1 agonist restores meningeal lymphatic vessels, drainage, and brain-CSF perfusion in craniosynostosis and aged mice

Abstract

Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We report that raised intracranial pressure and diminished CSF flow in craniosynostosis mouse models associate with pathological changes to meningeal lymphatic vessels that affect their sprouting, expansion, and long-term maintenance. We also show that craniosynostosis affects CSF circulatory pathways and perfusion into the brain. Further, craniosynostosis exacerbates amyloid pathology and plaque buildup in Twist1 +/– :5xFAD transgenic Alzheimer’s disease models. Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain-CSF perfusion. Leveraging these findings, we show that Yoda1 treatments in aged mice with reduced CSF flow and turnover improve lymphatic networks, drainage, and brain-CSF perfusion. Our results suggest that CSF provides mechanical force to facilitate meningeal lymphatic growth and maintenance. Additionally, applying Yoda1 agonist in conditions with raised intracranial pressure and/or diminished CSF flow, as seen in craniosynostosis or with ageing, is a possible therapeutic option to help restore meningeal lymphatic networks and brain-CSF perfusion.

Yoda1 opens the lymphatic path for craniosynostosis therapy

“…Matrongolo et al showed that treatment of Twist1 +/– mice exhibiting CS with Yoda1 reduced ICP and improved paravascular CSF-brain influx, MLV coverage, and CSF macromolecule clearance to dcLNs ( Figure 1 ). A similar beneficial effect of Yoda1 was also observed in aged mice that had undergone atrophic and hyperplastic changes in MLVs ( 12 ). These data indicate that Piezo1 activation is beneficial in the treatment of CS-associated ICP increase and that it can also rejuvenate age-related MLV changes ( 12 , 14 ).…”

“…A similar beneficial effect of Yoda1 was also observed in aged mice that had undergone atrophic and hyperplastic changes in MLVs ( 12 ). These data indicate that Piezo1 activation is beneficial in the treatment of CS-associated ICP increase and that it can also rejuvenate age-related MLV changes ( 12 , 14 ).…”

“…The study of Matrongolo et al ( 12 ), along with the findings of Ma et al ( 21 ), constitute a notable contribution to our understanding of the mechanisms responsible for increased ICP in CS, particularly in patients afflicted with the Saethre-Chotzen syndrome. Both studies indicate anatomical and functional defects in MLVs as a contributor to the CS disease pathology.…”

“…Notably, Matrongolo et al ( 12 ) unveil that Yoda1 holds promise in enhancing MLV structure and function. Although the effects of Yoda1 are pleiotropic because the Piezo cation channels are expressed by several cell types in various tissues, it may be possible to further develop Yoda1-related compounds for more specific targeting of LVs.…”

“…In this issue of the JCI , Matrongolo et al showed that Twist1 -haploinsufficient CS mouse models (both Twist1 +/– mice and Twist1 fl/+ ;Sm22a-Cre mice) exhibited increased ICP that correlated with dorsal MLV defects and impaired transfer of CSF tracers into MLV hotpots with poor subsequent drainage into dcLNs ( 12 ). Twist1 +/– CS mice did not develop CV malformations, unlike in the more severe models, such as in the Twist1 fl/– ;Sm22a-Cre mice, indicating that the increase in ICP does not always require CV malformations.…”