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Bischoff Laboratory | Current Research

Project One

Infantile hemangioma is a vascular tumor that can grow rapidly, causing organ damage, disfigurement and morbidity. My lab has focused on the cellular mechanisms that drive this uncontrolled vascular growth. In 2001, we showed that hemangioma-derived endothelial cells are clonal and exhibit abnormal properties. This suggests that hemangiomas are initiated from a single abnormal progenitor cell. Since then we have isolated increasingly less differentiated cells from hemangioma tissue, which led us to the identification of a multi-potent stem cell that can recapitulate hemangioma in immune-deficient mice. Therefore, vasculogenesis appears to play a major role in the formation of this common childhood tumor.

We have two major goals this project. The first is to understand the mechanisms that control the differentiation of the hemangioma stem cells into endothelial cells, pericytes and adipocytes.  This research may shed light on human post-natal vasculogenesis.  The second is to understand how endothelial-pericyte interactions in hemangioma may contribute to the spontaneous involution of the tumor, because to date, the mechanisms of hemangioma involution remain a mystery. 

Project Two

vascular malformations are defects in the architecture and function of arteries, veins, capillaries and lymphatic vessels. The malformations can be familial or sporadic, and are often associated with tissue overgrowth, deformity and infections.  We are focusing on capillary malformations (CM), which consist of excessive and abnormal capillary/venule-like vessels.   Sturge-Weber syndrome (SWS) is a rare neurological disorder that is strongly associated with CM.  In SWS patients, CMs of variable size are located on one or both sides of the face, typically on the upper eyelid and forehead.  In addition, excessive abnormal vessels are found on the surface of the brain and are thought to contribute to the neurologic deficits in children with SWS. 

A somatic, activating mutation in GNAQ (p.R183Q) was discovered in patients with SWS and CM, linking the vascular defect in these two disorders. We fractionated CM lesions into specific cell populations that were then genotyped for the GNAQ (p.R183Q) mutation.  Our new study shows that the GNAQ (p.R183Q) mutation is enriched in the endothelial cells of CM.  This identification the cellular context in which the molecular defect resides provides an essential foothold to investigate how CMs form, how to prevent CM and how to regress CM.  

Project Three 

Endothelial progenitor cells - EPCs - are a controversial area of research, in part because they are rare cells that can be difficult to identify.  EPCs are also called ECFC, for endothelial colony forming cell, which highlights an important feature of EPC/ECFC - robust proliferation in vitro.  We isolated EPC/ECFC that proliferate rapidly in vitro and form functional blood vessels in vivo from human cord blood and adult peripheral blood. We use these human ECFC combined with human mesenchymal progenitor cells (MPC), isolated from cord blood or from bone marrow, to build stable, perfused vascular networks in vivo rapidly - within 3-4 days.  We further showed that ECFC + MPC injected into ischemic myocardium (1) formed perfused vessels and (2) lead to significant improvements in heart function over 4 months.   These studies indicate that human ECFC have potential to contribute to tissue repair and regeneration.

Project Four 

We also study the plasticity of cardiac valve endothelium. We showed that valve endothelial cells from aortic, pulmonic and mitral valves can recapitulate processes that occur during valve development such as endothelial to mesenchymal transition (EndMT). We propose that the EndMT-competent cells along the valve endothelium are valve progenitor cells and that their job is replenish the valve interstitial cells on an as-needed basis throughout adult life and possibly during valve disease.  We are studying EndMT in the mitral valve to determine the extent to which EndMT might be part of the adaptative mechanism to limit mitral regurgitation after myocardial infarction. 

Hemangioma-derived stem cells form adipocytes two months after implantation in vivo (from Khan, Boscolo et. al., J. Clin. Invest. 2008.)  

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