Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response [1]

The bone marrow (BM) niche comprised of BM endothelial cells (BMECs) and LepR+ mesenchymal stromal cells (MSCs), plays a critical role in preserving the fitness of hematopoietic stem cells (HSCs). Aging is associated with defects in the BM niche that impair their ability to support HSC activity. However, mechanisms underlying age-related defects in the BM niche remain poorly understood. In this study, we identify BM niche derived Netrin-1 (NTN1) as a critical regulator of BM niche cell fitness during aging. Conditional deletion of NTN-1 specifically within BM MSCs or BMECs of young mice resulted in premature aging phenotypes within the BM niche including increased vascular leakiness, hypoxia, DNA damage and adiposity. On the other hand, supplementation of aged mice with NTN1 resulted in restoration of these hallmark niche defects and a rejuvenation of HSC activity. Mechanistically, we identify NTN1 as a critical regulator of DNA Damage Response (DDR) within BM niche cells and HSCs. In this experiment, RNA Seq analysis was performed on BM MSCs and BMECs following conditional deletion of NTN1 within BMECs or MSCs to characterize transcriptional alterations within BM niche cells resulting from a deficiency of niche derived NTN1. Overall design: Comparative gene expression profiling analysis of BM niche cells (BM MSCs and BMECs) following deletion of NTN1 in LepR+ MSCs (LepR_NTN1KO) or BMECs (CDH5_NTN1KO) of young (4-6 month old) mice.