Low-intensity pulsed ultrasound regulates proliferation and differentiation of neural stem cells through notch signaling pathway.
Wu Yu,Gao Qiang,Zhu Shibo,Wu Qiuli,Zhu Rusen,Zhong Hao,Xing Cong,Qu Haodong,Wang Dawei,Li Bo,Ning Guangzhi,Feng Shiqing
Biochemical and biophysical research communications
Low-intensity pulsed ultrasound (LIPUS) is widely used to regulate stem cell proliferation and differentiation. However, the effect of LIPUS stimulation on neural stem cells (NSCs) is not well documented. In this study, we have identified the optimal parameters, and investigated the cellular mechanisms of LIPUS to regulate the proliferation and differentiation of NSCs in vitro. NSCs were obtained and identified by nestin immunostaining. The proliferation of NSCs were measured by using Cell Counting Kit-8 (CCK-8). The expressions of nutritional factors (NTFs) were detected with immunoassay (ELISA). NSCs differentiation were detected by immunofluorescence and immunoblotting analysis. The expression level of proteins involved in the Notch signaling pathway was also measured by immunoblotting assay. Our results showed the intensity of 69.3 mW/cm (1 MHz, 8 V) was applicable for LIPUS stimulation. ELISA analysis demonstrated that LIPUS treatment promoted the expression of nutritional factors of NSCs in vitro. Immunofluorescence and immunoblotting analyses suggested that the LIPUS not only reduced the astrocyte differentiation, but also stimulated the differentiation to neurons. Additionally, LIPUS stimulation significantly upregulated expression level of Notch1 and Hes1. Results from our study suggest that LIPUS triggers NSCs proliferation and differentiation by modulating the Notch signaling pathway. This study implies LIPUS as a potential and promising therapeutic platform for the optimization of stem cells and enable noninvasive neuromodulation for central nervous system diseases.
10.1016/j.bbrc.2020.03.142
Ultrasound-induced blood-brain barrier disruption for the treatment of gliomas and other primary CNS tumors.
Beccaria Kévin,Canney Michael,Bouchoux Guillaume,Desseaux Carole,Grill Jacques,Heimberger Amy B,Carpentier Alexandre
Cancer letters
The treatment of primary brain tumors, especially malignant gliomas, remains challenging. The failure of most treatments for this disease is partially explained by the blood-brain barrier (BBB), which prevents circulating molecules from entering the brain parenchyma. Ultrasound-induced BBB disruption (US-BBBD) has recently emerged as a promising strategy to improve the delivery of therapeutic agents to brain tumors. A large body of preclinical studies has demonstrated that the association of low-intensity pulsed ultrasound with intravenous microbubbles can transiently open the BBB in a localized manner. The safety of this technique has been assessed in numerous preclinical studies in both small and large animal models. A large panel of therapeutic agents have been delivered to the brain in preclinical models, demonstrating both tumor control and increased survival. This technique has recently entered clinical trials with encouraging preliminary data. In this review, we describe the mechanisms and histological effects of US-BBBD and summarize the preclinical studies published to date. We furthermore provide an overview of the current clinical development and future potential of this promising technology.
10.1016/j.canlet.2020.02.013
Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound.
Rezai Ali R,Ranjan Manish,D'Haese Pierre-François,Haut Marc W,Carpenter Jeffrey,Najib Umer,Mehta Rashi I,Chazen J Levi,Zibly Zion,Yates Jennifer R,Hodder Sally L,Kaplitt Michael
Proceedings of the National Academy of Sciences of the United States of America
The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer's disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.
10.1073/pnas.2002571117