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Review
. 2008 Mar 1;7(3):523-9.
doi: 10.1016/j.dnarep.2007.11.012. Epub 2008 Jan 8.

DNA repair is crucial for maintaining hematopoietic stem cell function

Laura J Niedernhofer  1
Affiliations
Review

DNA repair is crucial for maintaining hematopoietic stem cell function

Laura J Niedernhofer. DNA Repair (Amst). .

Abstract

Richard Cornall and collaborators recently developed a mouse model of Ligase IV syndrome with growth retardation and immunodeficiency due to a defect in nonhomologous end-joining (NHEJ) of DNA double-strand breaks. They demonstrated age-dependent loss of hematopoietic stem cell function in these mice. Simultaneously, Irving Weissman and colleagues demonstrated a similar phenomenon in Ku80(-/-) mice defective in NHEJ and telomere maintenance, Xpd(TTD) mice defective in nucleotide excision repair, and late generation mTr(-/-) missing telomerase activity. These studies strongly support the hypothesis that genomic stress causes aging by limiting the ability of stem cells to indefinitely maintain tissue homeostasis.

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Figures

Figure 1
Figure 1
Schematic diagram of the linear hierarchy of hematopoietic cells. Cell surface markers used to identify each cell population are indicated with colored bars. Checked bars indicate surface markers with low expression. The blue color of the nuclei indicates the level of cell differentiation (dark blue indicating pluripotent cells; lighter blue indicating more committed cell lineages), which is correlated with proliferation rate (dark blue quiescent; lighter blue proliferating). Long term reconstituting hematopoietic stem cells (LT-HSCs) divide to produce a phenocopy of themselves (self-renewal) and a more committed multi-potent progenitor ST-HSC (short term reconstituting hematopoietic stem cell). ST-HSCs produce multi-potent progenitor cells (MPPs), which in turn produce lineage specific common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs).
Figure 2
Figure 2
Model of how hematopoietic stem cell function is lost as a consequence of unrepaired DNA damage. A. The bone marrow of young mammals contains relatively rare, quiescent long term reconstituting hematopoietic stem cells (LT-HSCs), multi-potent progenitors (ST-HSCs and MPPs) and more committed progenitors (CLPs and CMPs) as well as abundant terminally differentiated lymphoid and myeloid cells (unlabeled). Progenitors proliferate to produce more committed cells (arrows). DNA damage accumulates in the nuclei of cells with time (yellow dots). B. As differentiated cells need replacing, HSCs are recruited to proliferate. However, if DNA damage has accumulated in LT-HSCs, this impairs their function, preventing self-renewal and proliferation (red cross) or triggering apoptosis (green arrow). More committed cells that have accumulated genome damage are prone to apoptosis (green arrows) leading to depletion of these cell populations. C. The net result is hypocellularity and a relative enrichment of LT-HSCs harboring DNA damage in the bone marrow of aged organisms.
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