Notch signalling regulates stem cell numbers in vitro and in vivo

Abstract

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.

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

“…Second, depletion of stem cells is seen in the brains of mice lacking notch 1 or RBJkappa (Hitoshi et al, 2002). Third, there are increased numbers of newly-generated precursor cells following intraventricular injection of notch ligands (Androutsellis- Theotokis et al, 2006). Fourth, activation of either notch-1 or notch-3 in the forebrain results in increased numbers of (putative stem) cells with a radial glial phenotype (Gaiano et al, 2000;Dang et al, 2006).…”

Cellules souches neurales et signalisation Notch

“…Cependant, des observations apparemment discordantes concernant le rôle de Notch dans l'ischémie cérébrale demeurent. Ainsi, l'activation de la voie s'est révélée, d'une part, améliorer les paramètres fonctionnels dans un modèle murin d'occlusion de l'artère cérébrale moyenne [33], mais, d'autre part, prévenir la mobilisation des cellules épendymaires, les empêchant de donner naissance aux neuroblastes qui contribuent à la réparation des aires endommagées [27]. Ces discordances soulignent la nécessité d'une dissection très fine des mécanismes moléculaires impliqués et de leur dynamique temporelle en réponse à l'événement lésionnel avant de pouvoir envisager la signalisation Notch comme une cible thérapeutique dans ces pathologies.…”

“…Elle est aussi primordiale pour la prolifération des CSN de la ZSV et de la ZSG qui participent au processus de réparation. Cependant, au-delà de cette étape, une régulation négative de la signalisation Notch est ensuite nécessaire pour permettre aux nouveaux progé-Notch1 dans les CSN, la mise en jeu de signalisations indépendantes de RBPj comme Jak/Stat et Hes3 [33], ou l'activation de Notch par d'autres ligands que Jag1 [32]. Notch possède également un rôle additionnel dans la maturation des nouveaux neurones issus de la ZSG : il régule leur capacité à développer des neurites via le processus d'inhibition de contact [25,34].…”

Slow-Adhering Stem Cells Derived from Injured Skeletal Muscle Have Improved Regenerative Capacity

“…56,57 Moreover, STAT3 may be one of the downstream factors of Notch1 (Notch1-STAT3 signaling), which regulate stem cell characteristics. 58 Msx1 is a critical regulator of muscle development and regeneration that is primarily expressed in animals in the embryonic or fetal stage and is able to repress myogenic differentiation and maintain the undifferentiated status of stem cells. 59 -61 Both Pax3 and Pax7 are required for myogenic development, and are expressed in the somite; however, Pax7 is essential only for myogenesis after birth.…”

“…66,68 Up-regulated Notch1 and STAT3 signaling may contribute to improved proliferation capacity and multipotency of SASCs from injured muscle because both Notch1 and STAT3 are involved in stem cell maintenance and self-renewal. 54,55,58,69,70 Activation of Notch1 and STAT3 signaling pathways is also required for efficient muscle regeneration, 51,57 and their activation in SASCs from injured muscle may verify the highly regenerative potential and important function of this specific cell population in repairing injured muscle. In addition, the finding of activated Notch1 signaling in SASCs may suggest a promising contribution of the cells in therapeutic applications for regeneration of aged skeletal muscle.…”