Maternal diet alters long-term innate immune cell memory in fetal and juvenile hematopoietic stem and progenitor cells in nonhuman primate offspring

Maternal overnutrition increases inflammatory and metabolic disease risk in postnatal offspring. This constitutes a major public health concern due to the increasing prevalence of these diseases yet the mechanisms remain unclear. Here, using nonhuman primate models, we show that maternal Western-style diet (mWSD) exposure is associated with persistent pro-inflammatory phenotypes at the transcriptional, metabolic, and functional levels in bone marrow-derived macrophages (BMDMs) from 3-year-old juvenile offspring and in hematopoietic stem and progenitor cells (HSPCs) from fetal and juvenile bone marrow and fetal liver. mWSD exposure is also associated with increased oleic acid in fetal and juvenile bone marrow and fetal liver. ATAC-seq profiling of HSPCs and BMDMs from mWSD-exposed juveniles supports a model in which HSPCs transmit pro-inflammatory memory to myeloid cells beginning in utero. These findings demonstrate that maternal diet alters long-term immune cell developmental programming in HSPCs with proposed consequences for chronic diseases featuring altered immune/inflammatory activation across the lifespan. 3-year-old (3YO) juvenile Japanese macaque offspring were exposed to maternal control diet (mCD) or maternal western-style diet (mWSD) during gestation and lactation. At weaning, offspring were fed a mCD. Bulk RNA-seq was run for fetal and juvenile column-enriched bone marrow CD34+ cells (HSPCs) for differential gene expression. Chromatin changes assessed via ATAC-seq for genes in BMDM and HSPCs from mWSD and mCD for juveniles. Treatment/conditions represent: mCD= maternal CD (fetuses), mWSD = maternal WSD (fetuses), mCD/mCD = maternal CD and postweaning CD juveniles, and mWSD/mCD = maternal WSD and postweaning CD juveniles.