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Daily, cells incur tens of thousands of DNA lesions caused by endogenous processes. Due to their long‐lived nature, adult stem cells may be particularly susceptible to the negative impact of this constant genotoxic stress. Indeed, in murine models of DNA repair deficiencies, there is accumulation of DNA damage in hematopoietic stem cells and premature loss of function. Herein, we demonstrate that mice expressing reduced levels of ERCC1‐XPF DNA repair endonuclease ( Ercc1 −/Δ mice) spontaneously display a progressive decline in the number and function of hematopoietic stem/progenitor cells (HSPCs). This was accompanied by increased cell death, expression of senescence markers, reactive oxygen species, and DNA damage in HSPC populations, illustrating cell autonomous mechanisms that contribute to loss of function. In addition, the bone marrow microenvironment of  Ercc1 −/Δ mice was not permissive for the engraftment of transplanted normal stem cells. Bones from  Ercc1 −/Δ mice displayed excessive osteoclastic activity, which alters the microenvironment in a way that is unfavorable to HSPC maintenance. This was accompanied by increased proinflammatory cytokines in the bone marrow of  Ercc1 −/Δ mice. These data provide novel evidence that spontaneous, endogenous DNA damage, if not repaired, promotes progressive attrition of adult stem cells via both cell autonomous and nonautonomous mechanisms. S TEM  C ELLS  2013;31:511–525

Cell Autonomous and Nonautonomous Mechanisms Drive Hematopoietic Stem/progenitor Cell Loss in the Absence of DNA Repair