Project R-16358

Generating a multicellular "Organ-in-a-Dish" model to study Charcot-Marie-Tooth disease (Research)

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. However, despite significant advances in research, no effective treatment exists. The most prevalent subtype, CMT1A, results from PMP22 overexpression, leading to Schwann cell dysfunction, demyelination, and secondary axonal degeneration. An important obstacle in therapeutic development is the lack of physiologically relevant human models that replicate the complex multicellular environment of the peripheral nervous system (PNS). Although patient-derived iPSC-based models have significantly advanced the field, they are limited by complex reprogramming protocols, long differentiation times, and failure to achieve full maturation. Hence, they do not always successfully recapitulate the multicellular dynamics of the PNS. To overcome these limitations, we propose a novel, fully human "organ-in-a-dish" model of the PNS derived from dental pulp stem cells (DPSCs). These are neural crest–derived cells that can be obtained non-invasively from wisdom teeth, and differentiated efficiently into Schwann cells, motor neurons, and skeletal muscle, enabling the generation of genetically consistent, multicellular assembloids with cells derived from the same donor. DPSCs differentiate into Schwann cells more rapidly than iPSCs and exhibit a more mature phenotype, making them particularly suited for modelling myelin-related disorders such as CMT1A. This project combines the complementary expertise of Prof. Esther Wolfs (UHasselt) and Prof. Vincent Timmerman (UAntwerp) to develop, benchmark, and validate DPSC-based 3D neuromuscular assembloids as an "organ-in-a-dish" model for CMT1A. These will be compared to iPSC-based assembloids to evaluate cellular integration, functional maturation, and disease-specific phenotypes such as myelination defects, neuromuscular junction instability, and macrophage–glia interactions. This interuniversity GSKE project lays the foundation for a modular and adaptable in vitro platform for studying neuromuscular disease. While the current focus is on DPSC-only assembloids, we anticipate that combining the complementary strengths of DPSC- and iPSC-derived components will further enhance the physiological relevance and translational potential of the system.

01 January 2026 - 31 December 2028