Optimization of cell replacement therapy by modulating the brain microenvironment induced by needle trauma in Parkinson’s disease 3570

Description Parkinson’s disease (PD) is characterized by the progressive degeneration of midbrain dopamine (mDA) neurons within the substantia nigra, manifesting in profound motor and non-motor deficits. Our prior clinical trials demonstrated that autologous transplantation of patient’s iPSC-derived mDA progenitors (mDAPs) successfully circumvented immune rejection; however, modest cell survival and limited functional recovery highlighted suboptimal outcomes. Further investigation implicated intraoperative ‘needle trauma (NT)’ as a significant trigger of innate immune responses, compromising graft viability. In response, we developed intra-striatal co-transplantation strategy incorporating autologous regulatory T cells with mDAPs, which yielded enhanced outcomes. Mechanistic studies on NT revealed its profound impact on the brain microenvironment, identifying it as a critical factor in graft vulnerability and failure. Our research demonstrated that NT induces a cascade of immune responses, including the activation of key molecular and cellular pathways associated with inflammation and tissue damage. Through in-depth analysis, we uncovered specific mechanisms by which the inflammatory microenvironment compromises graft cell survival and therapeutic outcomes. Additionally, our findings highlight novel regulatory pathways that can be targeted to mitigate inflammation, providing a refined understanding of how to optimize brain microenvironment for improved cell replacement therapy in PD. Funding Sources This work was partially supported by NIH grants (NS127391 and NS129188), the Parkinson’s Cell Therapy Research Fund at McLean Hospital and Massachusetts General Hospital, and the Masson Family Endowed Scholar in Neurosurgery.