Multi‐Omics Reveals the Genetic and Metabolomic Architecture of Chirality Directed Stem Cell Lineage Diversification

Abstract Chirality‐directed stem‐cell‐fate determination involves coordinated transcriptional and metabolomics programming that is only partially understood. Here, using high‐throughput transcriptional‐metabolic profiling and pipeline network analysis, the molecular architecture of chirality‐guided mesenchymal stem cell lineage diversification is revealed. A total of 4769 genes and 250 metabolites are identified that are significantly biased by the biomimetic chiral extracellular microenvironment (ECM). Chirality‐dependent energetic metabolism analysis has revealed that glycolysis is preferred during left‐handed ECM‐facilitated osteogenic differentiation, whereas oxidative phosphorylation is favored during right‐handed ECM‐promoted adipogenic differentiation. Stereo‐specificity in the global metabolite landscape is also demonstrated, in which amino acids are enriched in left‐handed ECM, while ether lipids and nucleotides are enriched in right‐handed ECM. Furthermore, chirality‐ordered transcriptomic‐metabolic regulatory networks are established, which address the role of positive feedback loops between key genes and central metabolites in driving lineage diversification. The highly integrated genotype‐phenotype picture of stereochemical selectivity would provide the fundamental principle of regenerative material design.