Abstract
In adult mammals, hematopoietic stem cells (HSCs) reside in the bone marrow and are in part regulated by the bone marrow microenvironment, called the stem cell niche. We have previously identified the bone marrow morphogen osteopontin (OPN), which is abundantly present in the bone marrow extracellular matrix, as a negative regulator of the size of the HSC pool under physiological conditions. Here, we study the impact of OPN on HSC function during aging using an OPN-knockout mouse model. We show that during aging OPN deficiency is associated with an increase in lymphocytes and a decline in erythrocytes in peripheral blood. In a bone marrow transplantation setting, aged OPN-deficient stem cells show reduced reconstitution ability likely due to insufficient differentiation of HSCs into more mature cells. In serial bone marrow transplantation, aged OPN−/− bone marrow cells fail to adequately reconstitute red blood cells and platelets, resulting in severe anemia and thrombocytopenia as well as premature deaths of recipient mice. Thus, OPN has different effects on HSCs in aged and young animals and is particularly important to maintain stem cell function in aging mice.
Highlights
In mammalian tissues that undergo high cell turnover, such as hematopoietic system, a small population of stem cells maintains organ regeneration throughout the animal’s life span
Analyses of peripheral blood cell counts revealed a significantly reduced number of red blood cells in aged OPN−/− animals compared to age-matched controls (Fig. 1A), with no significant differences in platelet counts between the genotypes (Fig. 1B)
A differential analysis of white blood cells (WBCs) showed no differences between WBC subtypes in young animals (Fig. 1D) but a significant increase in both B and T lymphocytes in aged OPN−/− mice compared to age-matched controls (Fig. 1E,F), making these cell populations accountable for the increase in total leukocyte counts
Summary
In mammalian tissues that undergo high cell turnover, such as hematopoietic system, a small population of stem cells maintains organ regeneration throughout the animal’s life span. The functionality of stem cells declines during aging and can contribute to aging-associated impairments in tissue regeneration[1]. Accumulating evidence indicates that aged hematopoietic stem cells (HSCs) increase in number due to a higher rate of self-renewal cell divisions while displaying reduced intrinsic reconstitution ability[3,4,5,6,7]. A recent study showed that specimens of OPN-expressing cells displayed more evidence of aplastic anemia than did chronic myeloid leukemia specimens, suggesting that changes in the components of the bone marrow microenvironment contribute to impaired hematopoiesis[19]. In serial bone marrow transplants, OPN−/− stem cells are unable to sustain hematopoietic reconstitution beyond the second round of transplantation, resulting in deaths of recipients. In contrast to the known roles of OPN in young mice our data demonstrate different roles of OPN in aged and young animals
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