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

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. This research revealed that there is a distinct stereo-specificity in the overall composition of metabolites and in the regulatory networks that control gene expression and metabolic processes during L-extracellular microenvironment (ECM)-facilitated osteogenic and D-ECM-promoted adipogenic differentiation. The profound integration of genotype and phenotype pertaining to stereochemical selectivity holds the utmost importance in establishing the fundamental principle for regenerative material design.image