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Customer Article | Nature Communications (IF = 12.121): Senescent-like macrophages mediate endplate‑induced vascularization in male mice via IL‑10 secretion

　　Low back pain (LBP) is a global health issue that significantly impairs patients’ quality of life and imposes substantial burdens on healthcare resources and costs.

　　The cartilaginous endplate is located between the nucleus pulposus and the vertebral body; due to exposure to high shear stresses, it is prone to degeneration and injury. With aging or in the presence of other degenerative conditions, the cartilaginous endplate progressively undergoes sclerosis. Magnetic resonance imaging (MRI) findings of bone marrow lesions within the endplate are referred to as “Modic changes (MC)” and are strongly predictive of low back pain.

　　In earlier work, the team led by Ni Shuangfei at the First Affiliated Hospital of Zhengzhou University identified endplate sclerosis in lumbar spinal instability (LSI) and aging models, demonstrating that spinal pain is driven by sensory innervation of the porous regions within the sclerotic endplate. Recently, in a study published in Nature Communications titled “Senescent-like macrophages mediate angiogenesis for endplate sclerosis via IL-10 secretion in male mice,” they further showed that senescent‑like macrophages accumulate in the sclerotic endplates of aged mice. Moreover, deletion of cdkn2a (p16) in these macrophages abolishes both angiogenesis and endplate sclerosis induced by aging or lumbar spinal instability (LSI).

　　

 

　　Both in vivo and in vitro studies have demonstrated that IL‑10 is the predominant cytokine upregulated in the senescence‑associated secretory phenotype (SASP). Mechanistically, IL‑10 enhances pSTAT3 expression in endothelial cells, enabling pSTAT3 to directly bind to the promoters of Vegfa, Mmp2, and Pdgfb, thereby promoting their transcription and driving angiogenesis.

　　Research findings

　　| CD31Emcn: The coupling of vasculature with LSI and endplate sclerosis in aged mice

　　

 

　　The authors first investigated the role of CD31+Emcn+ vessels in endplate sclerosis associated with lumbar spinal instability (LSI) or aging in mice. Using immunofluorescence, three-dimensional micro-computed tomography (micro-CT), and ponceau S–fast green staining, they demonstrated that the endplates undergo increased osteogenesis during degeneration, and that CD31+Emcn+ vessels are present in the sclerotic endplates of LSI‑affected and aged mice.

　　| Senescent cells accumulate in the sclerotic endplates of LSI mice and aged mice

　　

 

　　Using senescence‑reporter transgenic mice (Cdkn2a, or p16‑tdTom), we demonstrated that the number of tdTom‑positive cells in the endplate significantly increases after LSI. SA‑βGal staining, immunofluorescence, and qRT‑PCR analyses revealed that LSI induces senescence in endplate cells, and that the endplate undergoes cellular senescence with advancing age.

　　| Clearance of senescent cells in LSI and aged mice delays endplate sclerosis

　　

 

　　Dasatinib plus quercetin (D+Q) is a well‑characterized and widely recognized senolytic agent. Researchers administered D+Q to LSI‑operated mice and aged mice, respectively.

　　The results showed that the D+Q treatment significantly reduced the numbers of SA-βGal+ and tdTom+ cells in the endplates of mice following LSI surgery and in aged mice, inhibited LSI‑ and age‑induced angiogenesis, and markedly slowed the progression of endplate sclerosis.

　　| Abundant macrophages undergo senescence in the endplates of LSI mice and aged mice

　　

 

　　Immunofluorescence co‑labeling and flow cytometry demonstrated that senescent macrophages undergo senescence in degenerated endplates, potentially contributing to angiogenesis and endplate sclerosis within the endplate.

　　Knocking out cdkn2a (p16) in Lyz2+ cells can eliminate endplate sclerosis.

　　

 

　　To further elucidate the role of senescent-like macrophages in endplate sclerosis, the researchers crossed Lyz2-Cre mice with Cdkn2a (p16) Flox mice, generating a conditional knockout mouse model (Cdkn2aΔLyz2) in which Cdkn2a is specifically deleted in Lyz2-positive cells.

　　Immunofluorescence, micro-CT, and ponceau S–fast green staining results showed that specific knockout of Cdkn2a in Lyz2+ cells inhibits LSI‑mediated angiogenesis and sclerotic changes in the vertebral endplates.

　 　| Macrophage deficiency inhibits LSI or senescence‑induced endplate sclerosis

　　

 

　　The study found that the macrophage-depleting solution CL can prevent aging‑induced endplate angiogenesis and sclerosis. Furthermore, genetic or pharmacological depletion of macrophages in LSI‑treated mice or aged mice reduces the number of Trap‑positive osteoclasts in the endplates.

　 　| IL-10 secreted by senescent-like macrophages promotes angiogenesis in degenerative endplates.

　　

 

　　To further investigate the signaling pathways underlying IL‑10‑mediated angiogenesis, we first selected several angiogenesis‑related factors. qRT‑PCR, Western blot, and ChIP assays demonstrated that IL‑10 promotes the expression of VEGFA, MMP2, and PDGFB in endothelial cells via the pSTAT3/STAT3 signaling pathway, thereby facilitating angiogenesis.

　　Summary

　　This study has deepened our understanding of the relationships among immune aging, angiogenesis, and endplate sclerosis, and it reveals that endplate sclerosis driven by senescent macrophages may represent a potential therapeutic target for spinal degeneration. These findings offer new insights into the link between immune aging and vertebral endplate sclerosis and hold significant implications for the development of novel treatments.

　　The 2–19-month-old C57BL/6J mice used in the aging experiments were provided by Aniphe BioLab.

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