The Hematopoietic stem cell population resident in bone marrow is responsible for generating blood cells and immune cells. Like all stem cell populations, their activity alters and declines with aging. This is one of the causes of the progressive disarray of the immune system in older individuals. If we want to rejuvenate the immune system, then restoring the youthful activity of hematopoietic stem cells is one of the items on the to-do list, alongside regrowth of the thymus, and clearing out the accumulation of exhausted, senescent, and misconfigured immune cells.
The protein osteopontin appears to have a sizable role in maintaining the hematopoietic stem cell population, but levels fall in older individuals. Researchers have demonstrated, in mice, that restoring high levels osteopontin can also restore a significant degree of hematopoietic stem cell activity. This is promising because it is comparatively simple to achieve and package as a therapy, but equally it isn't addressing whatever root causes underlie this narrow view of the picture. The open access paper here continues the investigation of osteopontin in the context of hematopoietic aging in mice, adding further evidence for its relevance.
In mammalian tissues that undergo high cell turnover, such as the hematopoietic system, a small population of stem cells maintains organ regeneration throughout the animal's life span. However, the functionality of stem cells declines during aging and can contribute to aging-associated impairments in tissue regeneration. 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 ability to reconstitute the immune system.
The phosphorylated glycoprotein osteopontin (OPN) is an extracellular matrix component of the bone marrow with important roles in tissue homeostasis, inflammatory responses, and tumor metastasis. The expression of OPN within the bone marrow is highly restricted to the endosteal surface, a location where HSCs have been found to reside preferentially. OPN binds to cells through integrins or the CD44 receptor, subsequently activating multiple signaling pathways. When HSCs are transplanted into wild-type (WT) or OPN knockout mice, they exhibit aberrant attachment and engraftment, suggesting the dependence of HSCs on OPN in these processes. Moreover, OPN deficiency within the bone marrow microenvironment results in an increase in primitive HSC numbers. More recently it has been reported that osteopontin exposure to aged HSC can attenuate their aging-associated phenotype.
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 ability to reconstitute the immune system likely due to insufficient differentiation of HSCs into more mature cells. In serial bone marrow transplantation, aged OPN knockout 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.