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

被引：22

作者：

Cho, Joon Seok ^{[1
,2
]}

Kook, Sung Ho ^{[1
,2
]}

Robinson, Andria Rasile ^{[1
,4
]}

Niedernhofer, Laura J. ^{[1
,3
]}

Lee, Byeong-Chel ^{[1
,2
]}

机构：

[1] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Pittsburgh, PA USA

[2] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA

[3] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA USA

[4] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

来源：

STEM CELLS | 2013年 / 31卷 / 03期

关键词：

Progerias; Aging; Stem cell; Nich; Oxidative DNA damage; STEM-CELL; BONE-MARROW; OXIDATIVE STRESS; PROGENITOR CELLS; MOUSE MODEL; LIFE-SPAN; MICE; AGE; ENDONUCLEASE; ERCC1-XPF;

D O I：

10.1002/stem.1261

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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-/Delta 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-/Delta mice was not permissive for the engraftment of transplanted normal stem cells. Bones from Ercc1-/Delta 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-/Delta 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. STEM CELLS 2013;31:511-525

引用

页码：511 / 525

页数：15