Low-intensity Ultrasound Promotes Brain Organoid Integration and Improves Microcephaly Defects

Background of the Study

Brain organoids are generated through the differentiation of pluripotent stem cells (PSCs) and exhibit impressive cellular diversity, capable of mimicking functional networks similar to the human brain. These organoid methods hold great potential for modeling neurological disorders and brain repair. However, the impact of physical stimulation on their development and integration remains unclear. This study aims to investigate the effects of low-intensity ultrasound (LIUS) on brain organoids.

Source of the Study

The research was a collaborative effort by multiple scholars from Tianjin University, published in 2024 in the journal Brain (Oxford University Press).

Research Process

The study included the following processes: 1. Generation of Brain Organoids: Cortical organoids were generated based on established protocols and exposed to LIUS starting on the 18th day. 2. Stimulation of Organoids at Different Intensity Ranges: It was found that ultrasound intensity of 0.2 W produced significant effects, and various aspects of organoid development were examined over time. 3. Transplantation Experiments: Pre-treated and untreated organoids were transplanted into the cerebral cortex of adult rats, observing their long-term effects at the injury site, including electrophysiological, histological tests, and neural connections. 4. Ultrastructural Dissection and Gene Analysis: A comprehensive assessment of organoid development changes was conducted using multiple methods, including immunohistochemistry, bulk RNA-seq, and single-cell RNA sequencing (scRNA-seq). 5. Exploration of Regulatory Mechanisms: The function of the YAP gene in organoids was explored through gene knockdown methods.

Main Findings

1. LIUS Promotes Organoid Growth: Experimental data indicated that organoids in the LIUS-treated group grew faster, had more compact tissue, and exhibited more active cell proliferation and neuronal differentiation.
2. Improved Post-transplantation Integration: Organoids showed increased cell area, enhanced neuronal maturity, and better integration and long-range projections when implanted in injured brain regions of rats.
3. The Important Role of the YAP Gene in LIUS Regulation: Knockdown of the YAP gene significantly weakened various aspects of organoid development and affected particle formation in primary microcephaly models.
4. LIUS Repairs ASP Gene Defect in Organoid Development: LIUS intervention significantly restored the growth and properties of ASP mutant model organoids.

Conclusion of the Study

The study demonstrates that LIUS significantly enhances neuronal differentiation and functional maturation of organoids, accelerates post-transplant integration with the host, and offers a potential non-invasive treatment for developmental disorders.

Highlights of the Study

This research shows the enhancement of organoid development and microstructural integration through the application of LIUS. Additionally, LIUS significantly repaired the genetic and developmental defects associated with ASP gene deletion and microcephaly, providing possibilities for future organoid repair studies.