Engineering Mesenchymal Stem Cell Spheroids and Brain Organoids: Advanced 3D Culture Platforms for Neurodegenerative Disease Cell Therapy.

Cell therapy for neurodegenerative diseases (NDs) is considered a promising strategy to halt disease progression. Currently, most clinically applied cells are derived from two-dimensional (2D) cultures. However, 2D-cultured mesenchymal stem cells (MSCs) are prone to aging and functional deterioration after multiple passages, and the availability of neural precursor cells for cell replacement therapy remains limited. In contrast, three-dimensional (3D) cell cultures have garnered significant attention due to their unique 3D spatial interactions. The unique spatial architecture of 3D culture not only enhances cell-cell and cell-extracellular matrix (ECM) interactions in MSC spheroids, thereby preserving MSCs properties, but also facilitates developmental processes of brain organoids derived from pluripotent stem cells, including embryogenesis, morphogenesis, and organogenesis. This review highlights the therapeutic ability of 3D-cultured MSC spheroids and brain organoids for NDs and summarizes advanced engineering platforms for their production. Future research should integrate the strengths of both technologies by establishing standardized quality control systems and scalable production processes to harness the microenvironmental modulation capacity of MSC spheroids and the precise cell replacement ability of brain organoids, ultimately advancing personalized therapies for NDs.