Matrix-bound Cyr61/CCN1 is required to retain the properties of the bone marrow mesenchymal stem cell niche but is depleted with aging

• Published in: Matrix biology 2022-08, Vol.111, p.108-132
• Main Authors: Marinkovic, Milos, Dai, Qiuxia, Gonzalez, Aaron O., Tran, Olivia N., Block, Travis J., Harris, Stephen E., Salmon, Adam B., Yeh, Chih-Ko, Dean, David D., Chen, Xiao-Dong
• Format: Article
• Language: English
• Subjects: Adult; Aging; Aging - genetics; Animals; Bone density; Bone loss; Bone marrow; Bone Marrow Cells; Bone microenvironment; Bone mineral density; Bone morphogenetic protein 2; Cell Differentiation; Cell Proliferation; CYR61 protein; Cyr61/CCN1; Cysteine-Rich Protein 61 - genetics; Cysteine-Rich Protein 61 - metabolism; Extracellular matrix; Geriatrics; Growth factors; Humans; Insulin-like growth factor I; Intercellular Signaling Peptides and Proteins - metabolism; Mesenchymal Stem Cells; Mice; Microenvironments; Middle Aged; Osteogenesis; Osteogenic differentiation; Proteomics; Proteomics - methods; Stem Cell Niche; Stem cell transplantation; Stem cells; Stromal cells; Therapeutic targets; Vertebrae
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2022.06.004

•A novel in vitro model was used to study ECM components which are responsible for the properties of the stem cell niche.•ECMs produced by stromal cells from young and elderly donors were different in proteomic composition and architecture.•Compared to young ECM, elderly ECM lacked Cyr61/CCN1 and did not support MSC proliferation or response to growth factors.•Elderly cells transfected with Cyr61/CCN1 produced an ECM with functionality (e.g. MSC proliferation) similar to young ECM.•The results indicate that Cyr61/CCN1 performs an essential function in the stem cell niche, which is lost during 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 y/o) versus “elderly” (≥60 y/o) 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, 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 resp