Cell-matrix biology of the vascular progenitor cell niche.

Diseases of the heart and blood vessels are one of the major causes of illness and death in Western society, and they represent a huge healthcare burden. This proposal is characterise a particular type of immature tissue repair cell, termed mesenchymal progenitor cell (or ?MPC?), and then exploit them to repair damaged hearts and regenerate blood vessels. Not only do MPCs have great therapeutic potential, but they can be expanded and analysed in the laboratory. Although clinical trials of transplanted MPCs into damaged hearts have been encouraging, limited understanding of their underlying biology remains a major obstacle to realising their therapeutic potential. Our timely proposal is to define their ?molecular signatures? and generate a comprehensive (open access) database of MPC marker molecules, determine how they regulate cell fate, and test how MPCs repair damaged blood vessels and injured hearts.

This proposal is to define the cell-extracellular matrix biology of the vascular mesenchymal progenitor cell (MPC) niche, as a basis for developing effective new cardiovascular therapies. MPCs offer immense opportunities for treating cardiovascular disease, given their accessibility, immunosuppressive and anti-inflammatory properties, paracrine contributions to tissue repair and potential to differentiate along vascular lineages. However, their underlying biology remains poorly defined and a major obstacle to realising their therapeutic potential. Signals across the cell-matrix interface control numerous aspects of cell biology, including survival, proliferation, migration and differentiation. This timely interdisciplinary proposal is to exploit our combined unique international strengths in cell-matrix and mesenchymal progenitor cell biology, state-of-the-art proteomics and glycomics, and in vivo models to define the MPC cell-matrix niche and apply this knowledge therapeutically. We will undertake systematic analysis to define the cell-matrix niche of MPCs from bone marrow and umbilical cord, generating a comprehensive (open access) database. This knowledge will allow us to determine how cell-matrix niche molecules control MPC fate decisions, to select MPCs reproducibly and track them during vascular regeneration in vivo, and to exploit the niche to enhance MPC-mediated repair of damaged blood vessels in injured hearts and the performance of engineered vascular grafts. Our studies will underpin a future pipeline of interlinked basic and translational studies of lead target proteins as determinants of cell fate and MPC-based cardiovascular therapies. The ultimate goal is to direct revascularisation of ischaemic heart and peripheral tissues. Thus, we offer a timely and exceptional opportunity to advance novel progenitor cell therapies for cardiovascular repair.