Human stem cell models in cerebral cavernous malformations

Cerebral cavernous malformation (CCM) is a rare cerebrovascular disorder characterized by abnormal endothelial architecture and clinically manifests as hemorrhage, epilepsy, and neurological deficits. Two primary factors have constrained the advancement of research in the field of CCM. Firstly, the utilization of animal models, which do not fully recapitulate human neurovascular biology, has been a major impediment. Secondly, the restricted access to patient lesion tissue has hindered progress. These constraints impede mechanistic dissection and therapeutic translation. This review discusses how models derived from human pluripotent stem cells (hPSCs), particularly induced pluripotent stem cells (iPSCs), are advancing research on cardiovascular endothelial cells by enabling human-specific and patient-tailored disease modeling. These stem cell models complement classical mouse models, creating a synergistic approach. The following section summarizes recent advances in three key areas: disease etiology, model development, and translational applications. In particular, the iPSC-derived endothelial cell system has provided mechanistic insights into how mutations in CCM1/2/3 and PIK3CA disrupt endothelial homeostasis in both two-dimensional and three-dimensional contexts, leading to aberrant activation of downstream signaling pathways. The discussion extends to more advanced platforms, including vascular organoids and blood-brain barrier models that more faithfully recapitulate the neurovascular microenvironment and pathological cell-cell interactions. Furthermore, iPSC-based high-throughput drug screening facilitates target validation, drug repurposing, and the development of personalized therapeutic strategies. Although challenges remain regarding model maturity and standardization, stem cell-derived vascular models provide a robust framework for CCM research. This review provides a concise overview of the fundamental iPSC models frequently employed in CCM research and proposes a hierarchical mechanistic framework of "mutation-driven, signal amplification, and lesion evolution." The advantages of 2D and 3D iPSC models for elucidating early endothelial abnormalities, cell-cell interactions, and tissue-level lesion formation are highlighted, and the applicability of various models for reconstructing the CCM microenvironment is emphasized. In conclusion, a model selection strategy for translational research is proposed: iPSC models should be used to elucidate human-derived mechanisms and for drug screening, while animal and chimeric models should be employed to study long-term disease progression, immune involvement, and in vivo validation.