ArticleMatrix biology : journal of the International Society for Matrix Biology2022
Matrix-bound Cyr61/CCN1 is required to retain the properties of the bone marrow mesenchymal stem cell niche but is depleted with aging.
Article in Matrix biology : journal of the International Society for Matrix Biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 27 citations in OpenAlex.
- Critical role of cellular communication network factor 1 in early osteogenesis of mesenchymal stem cells primed by low-intensity pulsed ultrasound and bone morphogenetic protein 2.Journal of cell communication and signaling · 2026Article
- Microenvironment-mediated stem cell fate in periodontal tissue remodeling and repair.Bioactive materials · 2026Review
- Paracrine Induction of Cardiomyogenic Differentiation in Patient-Specific MSCs Using Conditioned Medium from iPSC-CMs.Biomedicines · 2026Article
- Mesenchymal stem cell-derived extracellular matrix for musculoskeletal tissue regeneration.Communications biology · 2026Review
- CCN1 as a compartment-specific biomarker of active microenvironmental remodeling: evidence from bone repair, aging, inflammation, and cancer.Frontiers in medicine · 2026Review
- Article
- CCN Proteins as Matricellular Regulators of Bone in Aging and Disease.Current osteoporosis reports · 2025Review
- CYR61 delivery promotes angiogenesis during bone fracture repair.NPJ Regenerative medicine · 2025Article
- The influence of cell source on the senescence of human mesenchymal stem/stromal cells.Human cell · 2025Review
- ECM Protein CYR61 Promotes Migration and Osteoblastic Differentiation of Irradiation BMSCs via Migrasomes.Stem cells international · 2025Article
- Single-cell transcriptome and crosstalk analysis reveals immune alterations and key pathways in the bone marrow of knee OA patients.iScience · 2024Article
- Emerging Landscape of Mesenchymal Stem Cell Senescence Mechanisms and Implications on Therapeutic Strategies.ACS pharmacology & translational science · 2024Review
- CHIP: a clonal odyssey of the bone marrow niche.The Journal of clinical investigation · 2024Review
- Extracellular matrices of stromal cell subtypes regulate phenotype and contribute to the stromal microenvironment in vivo.Stem cell research & therapy · 2024Article
- Mesenchymal Stromal Cell Secretome Is Affected by Tissue Source and Donor Age.Stem cells (Dayton, Ohio) · 2023Article
- Mesenchymal Stem Cell Senescence during Aging:From Mechanisms to Rejuvenation Strategies.Aging and disease · 2023Review
- Hedgehog signaling regulates bone homeostasis through orchestrating osteoclast differentiation and osteoclast-osteoblast coupling.Cellular and molecular life sciences : CMLS · 2023Article
- Autologous mesenchymal stem cells offer a new paradigm for salivary gland regeneration.International journal of oral science · 2023Review
- Cellular microenvironment: a key for tuning mesenchymal stem cell senescence.Frontiers in cell and developmental biology · 2023Review
- Extracellular matrix turnover in salivary gland disorders and regenerative therapies: Obstacles and opportunities.Journal of oral biology and craniofacial researchArticle
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Authors and funding
10 authors at 1 institution in 1 country.
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Abstract
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 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.
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