Application of human ES-derived vascular progenitor cells to elucidation of vascular development/differentiation and vascular regeneration medicine

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From human ES cells we identified and isolated "vascular progenitor cells;VPC", which can be differentiated into both endothelial cells(EC) and vascular smooth muscle cells(VSMC) and organize blood vessel structure in vitro. Human ES cell-derived VPC(hESC-VPC) are TRA-1-Flk1+VEcadherin-PDGFR+ cells. We also discovered that vasodilating peptides, natriuretic peptides and adrenomedullin(AM) can activate cGMP and cAMP cascade, respectively and promote vascular regeneration, by several gene-engineered mice for these peptides, which we developed and by adenovirus-mediated gene transfer technique. Furthermore, we demonstrated that AM potently induces endothelial differentiation of mouse ES cell-derived VPC. Transplantation of EC and VSMC at early differentiation stage induced construction of human blood vessels in vivo and enhanced local blood flow to exert therapeutic effectiveness in hindlimb ischemia model or skin ulcer model. By in vitro human vascular development system, using human VPC, we elucidated the gene expression profiling of human undifferentiated ES,VPC and EC or SMC at early differentiation stage. Furthermore, we developed new biomaterial for blood vessel walls and seeded ES cell-derived VPC onto it. VPC in the artificial blood vessel walls were demonstrated to be differentiated into EC and VSMC by pulsatile flow loading.