Regulation of human Hematopoietic Stem and Progenitor Cells (HSPCs) regeneration after genotoxic stress

DNA damaging agents, such as ionizing radiation (IR) and chemotherapy, are a mainstay of cancer treatments today. At the same time, hematopoietic toxicity is the major complication after IR and chemotherapy treatments. Damage to Hematopoietic Stem and early Progenitor Cells (HSPC) is the major reason for this toxicity. This is why it is urgent to find a way to ameliorate this damage. We utilize human umbilical cord blood and bone marrow derived CD34+ cells as a source of HSCPs and committed progenitors (CPs) to investigate molecular and physiological aspects of DNA damage response upon clinically relevant doses of IR exposure. A previous study from our laboratory found that irradiated HSPCs, but not lineage-committed progenitors (CPs), undergo rapid ATM-ASPP1-p53-Bcl-2 dependent apoptosis. Here we reveal that co-culturing of HSPCs with bone marrow stroma cells or different types abrogates IR-induced apoptosis in HSPCs for at least 96 hours. Of interest, HSPCs recruitment into cell cycle abolished stroma-mediated protection from IR-induced apoptosis. Most importantly, irradiated quiescent HSPCs co-cultured with stroma cells preserved their long-term regeneration potential. Experiments using HSPC repopulation assays in vivo, that aimed to validate our in vitro findings, are ongoing. By utilization of genomics and proteomics approaches, we are also aiming to identify factors that are responsible for apoptosis inhibition by stromal cells. We believe that our research may assist in preventing HSPCs decline after radiation therapy, an unresolved and urgent clinical problem.