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Novel Patient-Derived Stem Cell Model Of Cherubism Harboring Mutation In SH3BP2 Gene
Janina Kueper, MD1, Casey Tsimbal, BS1, Nikita Myers, BS1, Nikkola Carmichael, MSc2, Victoria Perroni, MBA2, Richard L. Maas, MD, PhD2, Leonard B. Kaban, DMD, MD3, Eric C. Liao, MD, PhD1.
1Center for Regenerative Medicine, Shriners Hospital for Children/Massachusetts General Hospital, Boston, MA, USA, 2Brigham and Women's Hospital, Boston, MA, USA, 3Massachusetts General Hospital, Boston, MA, USA.

PURPOSE:
Cherubism is a rare condition characterized by dysplastic growth of the jaw bones. Characteristically, the mandible and maxilla are affected, with expansion of poorly ossified bone early in life and formation of cyst-like vacuoles that expand, deform and weaken the jaw structures. This may partially recede in young adulthood, though many patients will continue being affected throughout their life. Males appear to be disproportionally affected by cherubism, which is frequently inherited in an autosomal dominant manner. Unfortunately, the effectiveness of debulking procedures such as surgical excision or recontouring of the jaws is limited by disease flares that can be precipitated by surgical intervention itself. Animal models of cherubism have shown little resemblance to patient's phenotypes, rendering them unsatisfactory models. In order to gain insight into the molecular pathogenesis of cherubism, we recruited a subject with recurrent disease for this study.
METHODS:
Whole exome sequencing was carried out on the subject and his parents. We subsequently reprogrammed peripheral blood mononuclear cells into induced Pluripotent Stem Cells (iPSC). After allowing the cells mature to passage 10, we confirmed the genetic stability, cellular pluripotency and genomic purity of our cells. We subsequently derived cells implicated in the human disease process from our quasi-embryonic patient cells in order to retrace the development of cherubism in vitro. We supplemented our downstream experimental design by performing all inquiries in a sex- and ethnicity- matched batch of healthy iPSC as a control.
RESULTS:
We were able to identify a missense A521C variant in the gene SH3BP2 as the likely cause of our patient's cherubism. This gene has been identified as the cause of over 80 % of all cases of the disease, and as such represents a large portion of the patient population. The reprogramming process into iPSC did not differ between the patient and his parents. Similarly, the differentiation of the patient's iPSC into mesenchymal stromal cells showed no significant differences. Subsequent uneventful tri‐lineage differentiation to examine the cell's capacity for adipogenesis, chondrogenesis, and most pointedly, osteogenesis, pointed toward a more specific role of SH3BP2 in the pathophysiology of cherubism.
CONCLUSION:
We established the first patient-derived stem cell model of cherubism, attempting to model the disease in a dish. Identifying the molecular pathophysiology that underlies this condition will allow us to develop a deeper understanding of the processes involved in this disease, as well as bone metabolism overall. Drug identification through small molecule screens possible in our disease model in a dish promises the ability for a pharmacologic prevention or intraoperative modulation of the disease in the future. This work underscores the importance of the interface of surgical care and basic science, by applying stem cell and chemical screening approaches, highlighting the unique advantage of craniofacial surgeon-scientists to improve patient care.


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