Mechanisms of Endothelial Cell Maturation and Vascular Quiescence in Infantile Hemangioma

• Applicant: Dr. Caroline Seebauer
• Subject Area: Otolaryngology, Phoniatrics and Audiology ; General Genetics and Functional Genome Biology ; Dermatology ; Pediatric and Adolescent Medicine ; Cell Biology
• Term: from 2019 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 434348933

Vascular anomalies comprise a broad spectrum of orphan diseases, which are congenital in nature and associated with dysfunctional vessel development. Due to histopathological criteria two entities are defined. Vascular tumors show pathologic cell proliferation, exhibit rapid postnatal growth and slow regression during late childhood. Nevertheless, they can cause life-threatening complications, like ulceration and bleeding. Vascular malformations do not undergo abnormal cellular turnover and grow proportionally with the individual. Most vascular malformations are caused by somatic activating mutations in endothelial cells, but much less is known about the genetic causes of vascular tumors. Infantile hemangiomas, the most common vascular tumor, currently are treated with propranolol, a nonselective adrenergic blocker. Propranolol is generally well tolerated, however, its mechanism is not yet revealed and concerning side effects are hypoglycemia, bradycardia and hypotension. The intended host laboratory of Professor Bischoff has discovered a hemangioma stem cell (HemSC) that recapitulates infantile hemangiomas in mice. Recently Professor Bischoff was able to demonstrate that propranolol inhibits SOX18 dependent HemSC to hemangioma endothelial cell (HemEC) differentiation. We hypothesize that all of the HemSC-to-HemEC differentiation, as well as the HemSC-to-HemPericyte differentiation is blocked by propranolol. To investigate the mechanism of action of propranolol in regard to endothelial cell maturation and vascular quiescence in infantile hemangioma we have 2 aims:I) Identification of mRNA and protein targets of propranolol in HemSC-to-HemEC/Pericyte differentiation by administration of different substrates (propranolol, Sm4, rapamycin and corticosteroids) during differentiation: we analyze how each drug changes the transcriptome by RNA-sequencing to identify critical pathways. We will select 2-3 top candidates identified by RNA-sequencing data to perform gain of function and loss of function studies. II) Testing the premise that SOX18 is required for HemSC to HemEC differentiation by knocking down endogenous SOX18 in HemSC: we will test HemSC with SOX18 knockdown and HemSC with a dominant-negative mutation in the SOX18 gene (SOX18 Ragged Opossum) in vivo to see effects on hemangioma vessel formation.As propranolol is the first line therapy for infantile hemangioma treatment, it is crucial to identify molecular pathways that regulate HemSC-to-HemEC/Pericyte differentiation. The identification of protein targets of propranolol will open up new treatment options for those patients who suffer from side effects or do not respond to propranolol treatment. The aim of this application is to receive a fellowship that allows me to be a member of Professor Bischoff´s group at the Vascular Biology Program at Boston Children's Hospital, Harvard Medical School, during an 8-month research period in order to collaborate on this promising research topic.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Joyce E. Bischoff, Ph.D.