3- Deciphering the regenerative properties of endothelial progenitors (endothelial colony-forming cells or ECFCs) in
Human endothelial colony forming cells (ECFCs) are circulating endothelial
progenitors that can be isolated from umbilical cord blood and peripheral blood. These highly proliferative cells possess
the unique property to form functional blood vessels in vivo upon transplantation, a property that makes them particularly
attractive as a regenerative therapy for vascular repair of ischemic tissue damage, including limb ischemia,
heart attack and stroke. However, our limited knowledge of the molecular mechanism through which
stem cells work to repair damaged blood vessels has thus far prevented their efficient use in the clinic.
Our goal here is
to decipher the cellular and molecular mechanisms of ECFCs-mediated vascular repair such that these cells can be modified
prior to transplantation to acquire novel desirable properties for vascular regeneration including increased migration, homing
and/or differentiation to form new blood vessels.
Recently, we identified a key role for the transcription factor
TAL1 in mediating the repair function of ECFCs. Through a detailed molecular study, we demonstrated that TAL1 recruits the
histone acetyltransferase p300 to activate the expression of genes controlling critical regulatory pathways linked to vascular
function including migration and adhesion. From these findings, we designed a novel therapeutic strategy based on ex vivo
treatment of ECFCs with the epigenetic drug trichostatin A (a histone deacetylase inhibitor) to increase the expression of
TAL1-dependent genes. We found that pre-treatment with TSA significantly improves the vascular repair property of transplanted
ECFCs in a mouse model of limb ischemia providing proof-of principle that the priming of ECFCs with “epigenetic drugs”
prior to transplantation is a valuable strategy to improve their regenerative function (Cell Stem Cell, 14(5):
We are currently pursuing
our studies on the Epigenetic Regulation of Endothelial Cell-mediated Vascular Repair (FEBS Journal, 282(9):
1605-1629, 2015). This project is performed in collaboration with Erik Suuronen (Heart Institute, Ottawa, ON) and
David Allan (Ottawa Hospital, ON).