Research projects

Familial cerebral cavernous malformations (FCCMs) are vascular malformations mainly located within the brain that can cause cerebral hemorrhages, seizures and strokes, or in the most severe cases, even patient death. Despite the severity of the lesions caused by loss-of-function mutations in one of three cerebral cavernous malformation (CCM) genes, the molecular mechanisms behind this dysregulated endothelial cell (EC) behavior have not been elucidated yet. In this project, our main goal is to develop an improved in vitro model using pluripotent stem cells to decipher the role of each CCM gene during endothelial cell-fate specification.

During this last year we have successfully fulfilled the four objectives set at the beginning of this ambitious project. Among the most outstanding achievements of this project, thanks to our novel approach through in vitro modeling through cell reprogramming, are: 1) the development for the first time of an in vitro model that recapitulates the pathogenesis; 2) identification of new functions of CCM genes both in endothelial specification and in pluripotency; 3) identification of new altered transcriptomic and epigenetic mechanisms in the absence of each of the three CCM genes; and 4) identification of possible therapeutic targets whose chemical manipulation alleviates key processes that are altered in the absence of the CCM function both in endothelial differentiation and in the control of the pluripotent cell state.

Together, we believe that our findings contribute to a better understanding of the molecular programs involved in cellular fate determination and identify potential therapeutic targets for pharmacological intervention to treat this rare, severe, and heretofore incurable human disease.