Androutsellis-Theotokis Andreas, Leker Ronen R, Soldner Frank, Hoeppner Daniel J, Ravin Rea, Poser Steve W, Rueger Maria A, Bae Soo-Kyung, Kittappa Raja, McKay Ronald D G
Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature. 2006 Aug 17;442(7104):823-6. doi: 10.1038/nature04940. Epub 2006 Jun 25.
The hope of developing new transplantation therapies for degenerative diseases is limited by inefficient stem cell growth and immunological incompatibility with the host. 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 cancer.
开发针对退行性疾病的新移植疗法的希望受到干细胞生长效率低下以及与宿主免疫不相容性的限制。我们在此表明，Notch受体激活通过快速激活包括丝氨酸/苏氨酸激酶Akt、转录因子STAT3和雷帕霉素哺乳动物靶标在内的细胞质信号，诱导特定靶基因毛状和分裂增强子3（Hes3）以及音猬因子（Shh）的表达，从而促进神经干细胞的存活。在小鼠体细胞和人类胚胎干细胞中，这些正向信号受到一种涉及p38丝裂原活化蛋白激酶的控制机制的拮抗。向成年大鼠脑内短暂给予Notch配体，可增加缺血性损伤后新生成的前体细胞数量并改善运动技能。这些数据表明，再生医学的两个核心目标——体外和体内干细胞扩增，可能通过Notch配体经由一条对发育和癌症至关重要的途径来实现。
