IPSC-BASED HUMANIZED MODELS REVEAL INTRINSIC OLIGODENDROGLIAL DYSFUNCTION ASSOCIATED WITH MULTIPLE SCLEROSIS SEVERITY

Multiple sclerosis (MS) is a heterogeneous demyelinating disease in which patient-specific intrinsic oligodendroglial dysfunction may influence disease progression and repair capacity. Using complementary humanized models, we aim to investigate such dysfunction across MS patients with distinct clinical forms. Human induced pluripotent stem cells (hiPSCs) from patients with primary progressive MS (PPMS) and relapsing-remitting MS (RRMS), and healthy donors, were differentiated into human glial progenitor cells (hGPCs) and oligodendroglial progenitor cells (hOPCs). hGPCs were transplanted into neonatal Shiverer immunodeficient mice to assess myelination under non-inflammatory conditions. In parallel, wild-type mice were used for in utero transplantation of hGPCs, followed by induction of experimental autoimmune encephalomyelitis (EAE) in adulthood, to model inflammatory demyelination. In addition, hOPCs were transplanted in an ex vivo model of demyelination involving fresh human cortical tissue, and seeded onto synthetic nanofibers exposed to proinflammatory cytokines as a complementary in vitro model. In the Shiverer setting, PPMS-derived hGPCs exhibited reduced oligodendroglial differentiation and impaired myelination, whereas control and RRMS-derived cells preserved oligodendroglial maturation and myelination potential. Consistently, under the inflammatory EAE conditions, PPMS-derived hGPCs showed decreased migration toward white matter lesions and an increased astrocytic fate. The in vitro nanofiber approach also revealed vulnerabilities in oligodendroglial maturation under inflammatory conditions. In the ex vivo model, RRMS-derived hOPCs efficiently engrafted and remyelinated human brain tissue, demonstrating the feasibility of this human-specific remyelination platform. The integration of hiPSC-derived hGPCs and hOPCs in vivo, ex vivo and in vitro reveals intrinsic oligodendroglial dysfunctions that correlate with patient disability in MS.