| Major Projects
in Joyce Bischoff’s Laboratory
Molecular and Cellular Basis of Hemangioma
Hemangioma is a tumor of endothelial cells that occurs in
infants. These tumors can grow rapidly, causing organ damage
and disfigurement and even threatening life. However, a fascinating
aspect of hemangioma is that all true hemangiomas regress
over the course of several years, beginning at one year of
age. In my laboratory, we are elucidating the cellular and
molecular mechanisms that drive this uncontrolled growth and
the spontaneous regression. If we succeed, we may be able
to develop treatments to prevent the growth and/or speed up
the regression. These treatments may be applicable to other
types of uncontrolled endothelial growth that contribute to
many other angiogenic diseases (cancer, diabetic retinopathy,
arthritis etc).
Using blood-derived endothelial progenitors
to repair cardiovascular defects.
Endothelial cells line the interior of the heart and all
of the blood vessels of the body. New endothelial cells are
needed for growth of organs and tissue, and also to maintain
a healthy vasculature. The source of these new endothelial
cells was long thought to be from pre-existing blood vessels,
but emerging new studies clearly demonstrate that endothelial
progenitors (young newly formed endothelial cells) are present
in the bone marrow and in the bloodstream. We have shown that
these endothelial progenitor cells can be isolated from 15-20
milliliters of peripheral blood and used to create small diameter
blood vessels. (This was done in a sheep model in collaboration
with Dr. John Mayer in Cardiac Surgery.)
Endothelial Cell Growth and Differentiation
in Seminlunar Heart Valves.
Properly formed heart valve leaflets are essential to achieve
unidirectional blood flow and prevent blood regurgitation,
thereby ensuring efficient oxygen delivery to tissues throughout
the body. Despite the critical role of the valves in heart
function, relatively little is known about the development
of the valves and even less about the cellular and molecular
processes that sustain valve function through adult life.
We showed that endothelial cells (EC) from adult pulmonary
and aortic valve leaflets exhibit valve specific properties
that are reminiscent of critical steps in embryonic valve
development. For example, in mice, development of the aortic
and pulmonary valves (also known as semilunar valves) is dependent
on the transcription factor NFATc1. We showed that in human
valve EC, NFATc1 nuclear translocation is required for maximal
VEGF-induced proliferation. We also reported that clonal populations
of adult valvular EC can be induced to undergo an endothelial-to-mesenchymal
transdifferentiation (EMT) that is reminiscent of what occurs
during formation of valve leaflets from the endocardial cushions.
We hypothesize that VEGF/NFATc1 signaling and EMT in endothelium
of post-natal valve leaflets provides a mechanism for repair
and regeneration of the leaflets throughout adult life. We
are using our heart valve endothelial cell culture models
to identify genes that control endothelial proliferation and
differentiation and to understand the interplay between proliferation
and differentiation pathways in cardiac valves.
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