Differences between human and rodent DNA-damage response in hematopoietic stem cells: At the crossroads of self-renewal, aging and leukemogenesis

Life-long blood regeneration is critically dependent on self-renewing multipotent hematopoietic stem cells (HSCs). These cells' nearly unlimited self-renewal potential and lifetime persistence in the body, in contrast to the committed progenitors (CPs), signifies the need for tight control of HSC genome integrity. Indeed, accumulation of unrepaired DNA damage in HSCs is associated with bone marrow (BM) failure and accelerated leukemogenesis. Recent findings have revealed striking differences in DNA-damage response (DDR) characteristics between HSCs and CPs, especially in their DNA-repair activities and propensity for apoptosis. However, the molecular basis and physiological significance of the HSC-specific DDR characteristics are only partially understood. This review will discuss current progress in understanding the role of cell-intrinsic DDR players and the cellular microenvironment in the regulation of HSC self-renewal. In addition, we will attempt to provide a critical analysis of the differences between human and murine models employed to study the DDR in hematopoiesis.