Cell Lineage Tracing: How DNA-Barcoding Technologies Reveal the Secrets of Ontogenesis

Abstract In modern biomedicine, there is an increasingly urgent need for high-resolution data on individual cell fates during ontogenesis—from the zygote to the formation of mature tissues—particularly within complex organs such as the heart, brain, and spinal cord. A detailed understanding of these processes will enable the design of novel approaches in tissue and cell engineering, opening new avenues for treating previously incurable diseases, including neurodegenerative, cognitive, and mental disorders. Among the most powerful tools for cell lineage reconstruction are genetic barcoding technologies, which form the focus of this review. Here, we trace the evolution of genetic barcoding from early fluorescent systems (Brainbow, Confetti) to state-of-the-art DNA-barcoding platforms based on programmable Cas9 and Cas12a nucleases (GESTALT, MEMOIR, CARLIN, DuTracer, among others). We analyze and compare their key architectural properties, capacities, and limitations, as well as their potential applications in developmental biology and regenerative medicine. Further advancements in genetic barcoding technologies hold promise for generating predictive disease models, validating novel pharmacological targets, and developing cell-based therapeutics. We anticipate that this review will be of broad interest to a diverse audience—including developers of cell and gene technologies, researchers in regenerative biomedicine and developmental biology, omics specialists, and investigators studying age-related, neurodegenerative, and oncohematological diseases—by providing a comprehensive overview of a foundational methodology for reconstructing cell lineages to address both fundamental and applied challenges across the biological and medical sciences.