Past, present, and future of cell replacement therapy for parkinson’s disease: a novel emphasis on host immune responses

The primary pathological feature of Parkinson's Disease (PD) is the selective loss of midbrain dopamine neurons (mDANs) in the substantia nigra, which has driven extensive research in cell replacement therapy (CRT) for over forty years. Fetal ventral mesencephalon (fVM)-based CRT has provided proof-of-concept and invaluable lessons, particularly highlighting the limited survival of implanted mDANs as a significant factor contributing to variable and often inefficient clinical outcomes. Despite considerable research, the mechanisms underlying the acute and extensive death of mDANs post-transplantation remain only partially understood. Advancements in stem cell technology have paved the way for human pluripotent stem cell (hPSC)-based CRT, with various hPSC sources—such as allogeneic human embryonic stem cells (hESCs), allogeneic induced pluripotent stem cells (hiPSCs), HLA-matched hiPSCs, and autologous hiPSCs—being explored for scalable production of transplantable mDA cells in current and upcoming clinical trials. However, several critical issues must be addressed for successful hPSC-based CRT: Improving mDAN Survival: The survival of implanted mDANs is a key issue, drawing lessons from fVM-based CRT. Strategies to enhance survival throughout the transplantation process are crucial. Addressing Risks Across CRT Phases: Understanding and mitigating the risks of cell death during the multiple phases and steps of CRT are essential. This includes addressing the acute host immune responses triggered by the surgical procedure, which significantly affect mDAN survival. Manipulating Host Immune Responses: Both adaptive and innate immune responses of the host must be managed effectively. Recent evidence highlights that the surgical procedure itself can trigger host innate immune responses, necessitating strategies to manipulate these responses to enhance mDAN survival and improve clinical outcomes. Even with the potential survival of grafted mDANs post-transplantation, they face challenges in the PD host environment, which includes neuroinflammation, α-synucleinopathy, and a limited supply of essential factors. This unfavorable environment complicates the prolonged survival and maturation of the transplanted neurons, underscoring the need for further research. Additionally, PD often involves degeneration of other types of neurons, such as noradrenergic and serotonergic neurons, leading to various non-motor deficits. Consequently, even the most successful hPSC-based CRT may not offer a cure for PD but is expected to be part of a comprehensive treatment strategy that includes novel drug treatments (e.g., anti-inflammatory and neuroprotective therapies) and gene therapy.