Changes in the Extracellular Matrix Affect Mesenchymal Stem Cell Function with Age
The extracellular matrix is constructed and maintained by cells, and provides structural and other support to the cell populations of a tissue. The extracellular matrix changes with age, and is of great importance to tissue function, but the details of extracellular matrix aging do not receive anywhere near the attention given to the biochemistry of cells. The arrangement of molecules of the extracellular matrix determines the structural properties of tissue, and changes such as cross-linking alter that in harmful ways, such as by reducing the elasticity of skin and blood vessel walls. It is more than just structure, however. Countless molecules in the extracellular matrix are recognized by cells and their presence or absence changes cell behavior, just like other forms of cell signaling.
In today's open access paper, researchers note one example of an extracellular matrix molecule, CYR61, that both declines with advancing age and appears necessary to support the function of mesenchymal stem cells in bone marrow. Stem cells reside in a niche in tissue, and the structure of that niche, and behavior of the supporting cells making up the niche, has great influence on stem cell function. Stem cell populations produce a supply of daughter somatic cells that support a tissue, but this supply is diminished with age. Given that this loss has detrimental effects on tissue function, and is likely a sizable contribution to degenerative aging as a whole, there is a keen interest in the research community in better understanding the mechanisms of stem cell aging.
Previously, we showed that extracellular matrices (ECMs), produced ex vivo by various types of stromal cells, direct bone marrow mesenchymal stem cells (BM-MSCs) in a tissue-specific manner and recapitulate physiologic changes characteristic of the aging microenvironment. In particular, BM-MSCs obtained from elderly donors and cultured on ECM produced by young BM stromal cells showed improved quantity, quality, and osteogenic differentiation. In the present study, we searched for matrix components that are required for a functional BM-MSC niche by comparing ECMs produced by BM stromal cells from "young" (≤25 years old) versus "elderly" (≥60 years old) donors.
With increasing donor age, ECM fibrillar organization and mechanical integrity deteriorated, along with the ability to promote BM-MSC proliferation and responsiveness to growth factors. Proteomic analyses revealed that the matricellular protein, Cyr61/CCN1, was present in young BM-ECM, but undetectable in elderly BM-ECM. To assess the role of Cyr61 in the BM-MSC niche, we used genetic methods to down-regulate the incorporation of Cyr61 during production of young ECM and up-regulate its incorporation in elderly ECM. The results showed that Cyr61-depleted young ECM lost the ability to promote BM-MSC proliferation and growth factor responsiveness. However, up-regulating the incorporation of Cyr61 during synthesis of elderly ECM restored its ability to support BM-MSC responsiveness to osteogenic factors such as BMP-2 and IGF-1.
We next examined aging bone and compared bone mineral density and Cyr61 content of L4-L5 vertebral bodies in "young" (9-11 m/o) and "elderly" (21-33 m/o) mice. Our analyses showed that low bone mineral density was associated with decreased amounts of Cyr61 in osseous tissue of elderly versus young mice. Our results strongly demonstrate a novel role for ECM-bound Cyr61 in the BM-MSC niche, where it is responsible for retention of BM-MSC proliferation and growth factor responsiveness, while depletion of Cyr61 from the BM niche contributes to an aging-related dysregulation of BM-MSCs. Our results also suggest new potential therapeutic targets for treating age-related bone loss by restoring specific ECM components to the stem cell niche.