TY - JOUR
T1 - Cell autonomous and nonautonomous mechanisms drive hematopoietic stem/progenitor cell loss in the absence of DNA repair
AU - Cho, Joon Seok
AU - Kook, Sung Ho
AU - Robinson, Andria Rasile
AU - Niedernhofer, Laura J.
AU - Lee, Byeong Chel
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
KW - Aging
KW - Nich
KW - Oxidative DNA damage
KW - Progerias
KW - Stem cell
UR - http://www.scopus.com/inward/record.url?scp=84874819726&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874819726&partnerID=8YFLogxK
U2 - 10.1002/stem.1261
DO - 10.1002/stem.1261
M3 - Article
C2 - 23097336
AN - SCOPUS:84874819726
SN - 1066-5099
VL - 31
SP - 511
EP - 525
JO - Stem Cells
JF - Stem Cells
IS - 3
ER -