Neuroinflammation and Graft Survival in Pluripotent Stem Cell-Derived Therapies for the Central Nervous System

Recently, Japan conditionally approved the first cell transplantation therapy for a central nervous system disorder using induced pluripotent stem cells as the source of dopaminergic progenitors to treat Parkinson's disease. This milestone was achieved almost 40 years after the first cell therapy trial for Parkinson's disease in Lund, Sweden, and 18 years after the first clinical trial using oligodendrocyte progenitors derived from pluripotent stem cells for spinal cord injury. In this review, we update the current state of development of cell therapies based on pluripotent stem cells for diseases of the central nervous system and discuss the potential effects of neuroinflammation on these cell therapies. Focusing on Parkinson's disease, we summarize data showing the functional relevance of tumor necrosis factor-alpha for the differentiation and viability of pluripotent stem cell-derived dopaminergic progenitors and its dual effects on endogenous dopaminergic neurons, as presented at the Second Meeting of the Latin American Glia Club, held April 7-9, 2025, in Buenos Aires, Argentina. In addition, we propose areas of cell transplantation in Parkinson's disease in which research efforts could be focused and present a cautionary note on the use of non-selective anti-tumor necrosis factor-α therapies alongside pluripotent stem cell-derived dopaminergic progenitor transplantation. Finally, we provide an in-depth list of TNF receptor agonists and antagonists and specific TNF-mediated cell-death inhibitors and discuss their properties as possible candidates for increasing dopaminergic progenitor survival after transplantation in patients with Parkinson's disease.