From neural loss to regeneration: modulating cell death to enhance pluripotent stem cell graft survival and integration

Cerebrovascular and neurodegenerative diseases rank among the leading causes of death worldwide and represent an increasing socioeconomic burden, particularly in aging populations. Pluripotent stem cell (PSC)-based therapies have emerged as promising strategies for replacing lost neurons and restoring neural circuits in disorders of the central nervous system (CNS). However, major barriers remain, including poor survival, limited integration, and variable functional maturation of transplanted cells. These challenges currently limit the reproducibility and clinical translation of PSC-based therapies. Here, we examine these barriers with a particular focus on ischemic stroke and Parkinson’s disease, two conditions that represent complementary models of acute and chronic neuronal loss and are among the most advanced indications for PSC-based transplantation. We discuss how programmed cell death signaling contributes not only to neuronal loss in these disorders but also to the limited survival of transplanted PSC-derived grafts. Building on this mechanistic framework, we highlight strategies that may improve graft survival and functional integration. Specifically, we propose an integrated approach that combines modulation of programmed cell death pathways, targeted activation of RAS signaling, optimization of mitochondrial health, and use of biocompatible scaffolds to support neuronal maturation and network integration. Together, these strategies provide a conceptual framework for improving the reliability and therapeutic efficacy of PSC-based cell transplantation therapies and accelerating their translation toward clinical application.