Metabolic Programming of Hematopoietic Stem Cell Function By Prenatal Folate

Folate metabolism regulates methylation, nucleotide biosynthesis, and mitochondrial metabolism – processes central to HSC development and function. Prenatal folate programs risk for adult-onset diseases including cardiovascular disease, obesity, and cancer, but the pathogenic mechanisms are poorly understood. We tested the hypothesis that prenatal folate programs risk for adult disease by altering HSC function and immune cell output from early life. Female mice were assigned to experimental folate diets to model population wide folate consumption: 0mg/kg (folate deficient, FD), 2mg/kg (folate control, FC) and 8mg/kg (folate supplemented, FS). Pregnant females were maintained on experimental diets through weaning and offspring were weaned onto standard chow. Folate manipulation altered fetal HSC metabolism, including higher mitochondrial membrane potential in FD HSCs and enhanced glycolysis in FS HSCs compared to FC. Prenatal exposure to both FD and FS diets was associated with sustained alterations to adult hematopoiesis, including expanded lymphopoiesis in both FD and FS offspring compared to FC. Serial competitive transplantation of adult offspring HSCs revealed that FD displayed limited self-renewal and lineage output, whereas FS enhanced self-renewal and total cellular output compared to FC. Metabolomic and transcriptional analysis of adult offspring HSCs revealed that these differences reflected sustained molecular alterations: FD HSCs exhibited increased glycolysis associated with glucose accumulation whereas FS HSCs exhibited increased serine metabolism associated with enhanced mitochondrial function and increased output by transplantation. Ongoing studies evaluate how prenatal folate shapes adult response to hematopoietic challenge. Our data suggest that prenatal folate reprograms HSC function into adulthood driven by fetal alterations to metabolic activity. Folate metabolism regulates methylation, nucleotide biosynthesis, and mitochondrial metabolism – processes central to HSC development and function. Prenatal folate programs risk for adult-onset diseases including cardiovascular disease, obesity, and cancer, but the pathogenic mechanisms are poorly understood. We tested the hypothesis that prenatal folate programs risk for adult disease by altering HSC function and immune cell output from early life. Female mice were assigned to experimental folate diets to model population wide folate consumption: 0mg/kg (folate deficient, FD), 2mg/kg (folate control, FC) and 8mg/kg (folate supplemented, FS). Pregnant females were maintained on experimental diets through weaning and offspring were weaned onto standard chow. Folate manipulation altered fetal HSC metabolism, including higher mitochondrial membrane potential in FD HSCs and enhanced glycolysis in FS HSCs compared to FC. Prenatal exposure to both FD and FS diets was associated with sustained alterations to adult hematopoiesis, including expanded lymphopoiesis in both FD and FS offspring compared to FC. Serial competitive transplantation of adult offspring HSCs revealed that FD displayed limited self-renewal and lineage output, whereas FS enhanced self-renewal and total cellular output compared to FC. Metabolomic and transcriptional analysis of adult offspring HSCs revealed that these differences reflected sustained molecular alterations: FD HSCs exhibited increased glycolysis associated with glucose accumulation whereas FS HSCs exhibited increased serine metabolism associated with enhanced mitochondrial function and increased output by transplantation. Ongoing studies evaluate how prenatal folate shapes adult response to hematopoietic challenge. Our data suggest that prenatal folate reprograms HSC function into adulthood driven by fetal alterations to metabolic activity.