Sonic Hedgehog signaling regulates vascular differentiation and function in human CD34 positive cells: vasculogenic CD34(+) cells with Sonic Hedgehog.

Identification of pivotal factors potentially present in the in situ environment and capable of influencing the function of CD34(+) cells, which can be used for autologous cell therapy, is of paramount interest. SHh is one of the morphogens essential for embryonic vascular development as well as postnatal neovascularization, and the activation of SHh signaling with angiogenic and vascular differentiation responses in CD34(+) cells by SHh treatment differed depending on the G-CSF treatment or the background disease. SHh enhanced the migration, proliferation, adhesion, and EPC colony forming capacities of G-CSF mobilized CD34(+) cells, increasing the vasculogenic/angiogenic potential for neovascularization. An increase in the differentiation potential of CD34(+) cells toward vascular lineages was demonstrated with SHh treatment involving TGFß signaling pathway. The SHh-activated G-CSF mobilized CD34(+) cells directly contributed to vascular regeneration while non-activated CD34(+) cells showed a lower regenerative capacity in a mouse ischemic hindlimb model. SHh signaling regulates human CD34(+) cell fate and function, and may potentiate the therapeutic effect of G-CSF mobilized CD34(+) cells on ischemic diseases.

Human cardiac stem cells with reduced notch signaling show enhanced therapeutic potential in a rat acute infarction model.

BACKGROUND: Because human cardiac stem cells (CSC) have regeneration potential in damaged cardiac tissue, there is increasing interest in using them in cell-based therapies for cardiac failure. However, culture conditions, by which CSCs are expanded while maintaining their therapeutic potential, have not been optimized. We hypothesized that the plating cell-density would affect proliferation activity, differentiation and therapeutic potential of CSCs through the Notch signaling pathway. METHODS AND RESULTS: Human CSCs were plated at 4 different densities. The population doubling time, C-KIT positivity, and dexamethasone-induced multidifferentiation potential were examined in vitro. The therapeutic potential of CSCs was assessed by transplanting them into a rat acute myocardial infarction (AMI) model. The low plating density (340cells/cm(2)) maintained the multidifferentiation potential with greater proliferation activity and C-KIT positivity in vitro. On the other hand, the high plating density (5,500cells/cm(2)) induced autonomous differentiation into endothelial cells by activating Notch signaling in vitro. CSCs cultured at low or high density with Notch signal inhibitor showed significantly greater therapeutic potential in vivo compared with those cultured at high density. CONCLUSIONS: CSCs cultured with reduced Notch signaling showed better cardiomyogenic differentiation and therapeutic potentials in a rat AMI model. Thus, reducing Notch signaling is important when culturing CSCs for clinical applications.