Yoda1 opens the lymphatic path for craniosynostosis therapy
Aleksanteri Aspelund, Kari Alitalo
Aleksanteri Aspelund, Kari Alitalo
Published February 15, 2024
Citation Information: J Clin Invest. 2024;134(4):e176858. https://doi.org/10.1172/JCI176858.
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Commentary

Yoda1 opens the lymphatic path for craniosynostosis therapy

Abstract

The rediscovery of meningeal lymphatic vessels (MLVs) has sparked research interest in their function in numerous neurological pathologies. Craniosynostosis (CS) is caused by a premature fusion of cranial sutures during development. In this issue of the JCI, Matrongolo and colleagues show that Twist1-haploinsufficient mice that develop CS exhibit raised intracranial pressure, diminished cerebrospinal fluid (CSF) outflow, and impaired paravascular CSF-brain flow; all features that were associated with MLV defects and exacerbated pathology in mouse models of Alzheimer’s disease. Activation of the mechanosensor Piezo1 with Yoda1 restored MLV function and CSF perfusion in CS models and in aged mice, opening an avenue for further development of therapeutics.

Authors

Aleksanteri Aspelund, Kari Alitalo

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Figure 1

Craniosynostosis mutations and Yoda1 affect LVs, brain-CSF perfusion and outflow, and ICP.

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Craniosynostosis mutations and Yoda1 affect LVs, brain-CSF perfusion and...
(A) In WT mice, CSF flows via MLVs to dcLNs along skull sutures. Twist1+/–, Twist1+/fl;Sm22a-Cre, and Fgfr2+/S252W mice display fused skull sutures, increased ICP, diminished paravascular CSF-to-brain (also known as glymphatic) flow, reduced perisinusoidal MLV coverage, and impaired CSF drainage to dcLNs, while still having normal CVs and middle meningeal artery–associated (MMA-associated) MLVs. Yoda1 treatment of Twist1+/– mice decreases ICP, restores CSF-to-brain flow, increases MLV coverage, and reinstates CSF drainage to the dcLNs (12). (B) Yoda1 interaction with Piezo1 facilitates the fluid flow–induced conformational changes in the Piezo1 cation channel, lowering its activation threshold mediated by calcium (Ca2+) influx (12). Piezo1 has also been shown to promote lymphatic endothelial cell (LEC) sprouting and expansion, functions that overlap with SPC-derived VEGF-C. VEGF-C binds to VEGFR-3, which additionally enhances lymphatic muscle cell (LMC) contractility, leading to increased lymph flow (23).