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

DNA damaging agents, such as radiation (IR) and chemotherapy, are a mainstay of most 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 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. Co-culturing of freshly isolated, quiescent HSPCs with bone marrow OP9M2 stroma cells can prevent the massive IR-induced apoptosis in HSPCs. Furthermore, we found that the contact of HSPCs with the stroma cells is critical, as its disruption greatly increases the apoptosis rate. In addition, we revealed that HSPCs recruitment into cell cycle upon ex vivo cultivation with cytokines followed by IR exposure, abolished stroma-mediated protection from IR-induced apoptosis. In my research, we are planning to examine whether forcing HSPCs to stay quiescent throughout the radiation treatment may save these highly important cells, and by that improve the therapeutic quality of the treatment given today. Moreover, by utilization of genomics and proteomics we are aiming to find the factor that is responsible for apoptosis inhibition by stromal cells. Taken together, this research may assist in preventing cell death after radiation therapy, an unresolved and urgent clinical problem.