Human Pluripotent Stem Cell-Based Therapies for Parkinson's Disease: Challenges and Potential Solutions.

Over 20 years of research on human pluripotent stem cell (hPSC)-based therapies for Parkinson's disease (PD) has recently culminated in clinical trials. The first clinical report on autologous transplantation of patient-derived hPSCs showed significant motor symptom improvement, validating the therapeutic promise of this approach. However, critical challenges remain, notably the limited engraftment and survival of donor cells. Cellular stress incurred during in vitro differentiation of hPSCs into midbrain dopaminergic progenitors and neurons contributes to the reduced survival of grafted mDA neurons. Additionally, the host brain environment at the injection sites becomes hostile to transplanted cells due to needle trauma, immune rejection, and alpha-synuclein pathology present in the brains of PD patients. This review discusses potential strategies to address both intrinsic donor cell stress and hostile host brain environment, aiming to enhance the long-term efficacy and engraftment of hPSC-based cell therapies for PD.