MSC implantation as a treatment for developmental brain defects in craniosynostosis

PROJECT SUMMARY/ABSTRACT Craniosynostosis is a craniofacial disorder, which is characterized by the premature fusion of cranial sutures with the loss of mesenchymal stromal/stem cells (MSCs). Some craniosynostosis have neurocognitive deficits, which are attributed to abnormally increased intracranial pression (ICP). However, the causes of ICP elevation and brain defects in craniosynostosis are poorly understood. The goal of this proposal is to establish novel mechanisms and a therapeutic strategy by which suture MSC implantation can lead to long-term reduction of ICP and reverse neurological deficits in craniosynostosis. The scientific premise is based on our recently published data (Cell, 2021, PMID: 33417861; Cell Stem Cell 2023, PMID: 37863055), in which we established the first animal model of neurological defects in craniosynostosis, identified meningeal lymphatic vessel (mLV) defect as a pathological driving factor for cognitive defects, developed a MSC-based suture regeneration approach, and used this approach and successfully rescued brain structure and function defects in Twist1+/- mice. This is significant because craniosynostosis is a major congenital disorder with a prevalence of 1 in every 2500 births. Previous animal research on craniosynostosis has mainly focused on skull dysmorphology, while brain and neurological defects have largely been neglected. Current clinical practice in treating craniosynostosis involves highly invasive complex surgery on calvarial bones at a very young age, with significant blood loss and often requires repeated surgeries to prevent bone re-fusion. Our MSC-based treatment provides several advantages over these practices, which include requiring only a single surgery at a focal cranial suture site with minimal invasiveness, as well as the ability to reverse both skull and neurological defects. To truly enable clinical translation, it is prudent to determine why MSC implantation has such robust benefits in correcting brain defects in craniosynostosis. Preliminary data identified two potential risk factors for ICP elevation, including meningeal lymphatic and cerebral vein defects. These defects might not be improved by the standard surgical operation in current clinics but can be corrected by MSC implantation, which is the focus of this proposal. Overall, building upon our strong preliminary data, this study seeks to provide the preclinical validation of MSC implantation as a better therapeutic strategy over the surgical approach in current clinical practice for brain deficits in craniosynostosis.