Cerebrospinal Fluid: From the Sacred River of the Brain to an Emerging Reservoir of Neural Stem and Progenitor Cells

Abstract

For centuries, cerebrospinal fluid (CSF) was regarded primarily as a protective and nutritive fluid surrounding the brain and spinal cord. Advances in developmental neuroscience, stem cell biology, and regenerative medicine have transformed this traditional view by demonstrating that CSF functions as a dynamic biological microenvironment enriched with growth factors, extracellular vesicles, cytokines, metabolites, and regenerative cellular populations. Emerging evidence suggests that CSF serves both as a critical signaling niche for neural stem cells and as a source of heterogeneous stem-like and progenitor cell populations that may contribute to central nervous system (CNS) development, homeostasis, and repair.

Unlike established stem-cell sources such as bone marrow, umbilical cord blood, or adipose tissue, the identity, origin, and functional significance of CSF-derived regenerative cells remain incompletely understood. Recent studies implicate multiple cellular sources, including the choroid plexus, ventricular-subventricular zone, ependymal-associated progenitors, and other periventricular stem-cell niches. Furthermore, growing recognition of the roles of the choroid plexus-CSF axis, glymphatic transport system, and age-associated changes in CSF composition has expanded our understanding of how the CSF microenvironment regulates neurogenesis and neurological health.

This review summarizes current knowledge of CSF-derived stem/progenitor cells, including their putative origins, biological properties, mechanisms of action, and potential applications in disease modeling, biomarker discovery, and regenerative medicine. We further highlight emerging engineering approaches, including choroid plexus organoids, biomaterial-based niche engineering, microphysiological systems, neural organoids, three-dimensional bioprinting, single-cell multi-omics, and artificial intelligence-driven analyses that may accelerate progress in the field. Finally, we discuss current challenges involving cellular identity, standardization, scalability, and clinical translation, as well as future opportunities for leveraging CSF-derived cellular and molecular components in precision neurology and next-generation regenerative therapies.