![]() Notably, BMP4 addition or Id3 silencing rescued the defective differentiation observed in Tis21-null neurospheres, indicating that they mediate the Tis21 pro-differentiative action. The ability, however, of neuroblasts to migrate from SVZ explants was not affected, suggesting that Tis21-null neuroblasts do not migrate to the olfactory bulb because of a defect in terminal differentiation. Correspondingly, the Tis21-null SVZ stem cells greatly increased nonetheless, the proliferating neuroblasts diminished, whereas the post-mitotic neuroblasts paradoxically accumulated in SVZ, failing to migrate along the rostral migratory stream to the olfactory bulb. Thus, in the SVZ Tis21 activates the BMP pathway and inhibits the Notch pathway and the cell cycle. Moreover, cyclins D1/2, A2, and E were strongly up-regulated. Consistently, expression of the proneural bHLH gene NeuroD1 decreased. In Tis21-null SVZ and cultured neurospheres, we observed a strong decrease in the expression of BMP4 and its effectors Smad1/8, while the Notch anti-neural mediators Hes1/5 and the basic helix-loop-helix (bHLH) inhibitors Id1-3 increased. Here we analyze the role at the intersection of these pathways of Tis21 ( Btg2/PC3), a gene regulating proliferation and differentiation of adult SVZ stem and progenitor cells. 4Libera Università Maria Sartissima Assunta, Rome, Italyīone morphogenic proteins (BMPs) and the Notch pathway regulate quiescence and self-renewal of stem cells of the subventricular zone (SVZ), an adult neurogenic niche.3Institute of Translational Pharmacology, National Research Council, Fondazione EBRI, Rome, Italy.2Department of Psychology and “Daniel Bovet” Center, Sapienza University of Rome, Rome, Italy.1Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, Rome, Italy.Gene Editing: Technology & Applications.Stefano Farioli-Vecchioli 1† Manuela Ceccarelli 1† Daniele Saraulli 1† Laura Micheli 1 Sara Cannas 1,2 Francesca D'Alessandro 1,2 Raffaella Scardigli 3 Luca Leonardi 1 Irene Cinà 1 Marco Costanzi 1,4 Andrea Mattera 1 Vincenzo Cestari 1,2 Felice Tirone 1* Salivary gland hypofunction causes significant morbidity and loss of quality of life for head and neck cancer patients treated with radiotherapy. ![]() Preventing hypofunction is an unmet therapeutic need. We used an adeno-associated virus serotype 2 (AAV2) vector expressing the human neurotrophic factor neurturin (CERE-120) to treat murine submandibular glands either pre- or post-irradiation (IR). Treatment with CERE-120 pre-IR, not post-IR, prevented hypofunction. RNA sequencing (RNA-seq) analysis showed reduced gene expression associated with fibrosis and the innate and humoral immune responses. We then used a minipig model with CERE-120 treatment pre-IR and also compared outcomes of the contralateral non-IR gland. Analysis of gene expression, morphology, and immunostaining showed reduced IR-related immune responses and improved secretory mechanisms. CERE-120 prevented IR-induced hypofunction and restored immune homeostasis, and there was a coordinated contralateral gland response to either damage or treatment. CERE-120 gene therapy is a potential treatment for head and neck cancer patients to influence communication among neuronal, immune, and epithelial cells to prevent IR-induced salivary hypofunction and restore immune homeostasis. Which was measured by pilocarpine stimulation of whole saliva production. Saliva was collected 90 days post-IR, and the IR control group produced ∼65% less saliva compared to the non-IR group (baseline), irrespective of whether the AAV2-GFP was delivered pre- or post-IR ( Figures 1C–1E). All CERE-120 treatments pre-IR (10 6, 10 8, 10 10 vp/g) resulted in improved saliva flow compared to the IR-GFP group and were similar to the non-IR group at 90 and 300 days. At 120 days, there were differences in the 3 doses with CERE-120 at 10 8 and 10 10 vp/g being similar to non-IR. In comparison, CERE-120 post-IR treatment groups only showed similar saliva flow to the non-IR group at 300 days, not at 90 and 120 days post-IR ( Figures 1C and 1D).
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