Notch signalling regulates stem cell numbers in vitro and in vivo

One barrier to using stem cells for therapies is the difficulty in controlling their growth and differentiation. Androutsellis-Theotokis et al. show that the Notch receptor plays a pivotal role in a pathway that controls the survival of embryonic, fetal and adult stem cells, and that administration of Notch ligands to the brains of adult rats can help the animals recover movement after a simulated stroke. The finding paves the way towards therapies that aim to encourage the body's endogenous stem cells to repair damage, rather than trying to grow and transplant new cells. The Notch receptor plays a pivotal role in a pathway that controls the survival of embryonic, fetal and adult stem cells, as it activates the phosphatidylinositol-3-OH kinase/Akt signalling pathway and identifies a key serine on STAT3. The hope of developing new transplantation therapies for degenerative diseases is limited by inefficient stem cell growth and immunological incompatibility with the host1,2. Here we show that Notch receptor activation induces the expression of the specific target genes hairy and enhancer of split 3 (Hes3) and Sonic hedgehog (Shh) through rapid activation of cytoplasmic signals, including the serine/threonine kinase Akt, the transcription factor STAT3 and mammalian target of rapamycin, and thereby promotes the survival of neural stem cells. In both murine somatic and human embryonic stem cells, these positive signals are opposed by a control mechanism that involves the p38 mitogen-activated protein kinase. Transient administration of Notch ligands to the brain of adult rats increases the numbers of newly generated precursor cells and improves motor skills after ischaemic injury. These data indicate that stem cell expansion in vitro and in vivo, two central goals of regenerative medicine, may be achieved by Notch ligands through a pathway that is fundamental to development and cancer3,4,5.