A novel LncRNA SPIRE1/miR-181a-5p/PRLR axis in mandibular bone marrow–derived mesenchymal stem cells regulates the Th17/Treg immune balance through the JAK/STAT3 pathway in periodontitis

Abstract

Periodontitis is a microbial-related chronic inflammatory disease associated with imbalanced differentiation of Th17 cells and Treg cells. Bone marrow-derived mesenchymal stem cells (BM-MSCs) possess wide immunoregulatory properties. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) contribute to the immunomodulation in the pathological mechanisms of inflammatory diseases. However, critical lncRNAs/miRNAs involved in immunomodulation of mandibular BM-MSCs largely remain to be identified. Here, we explored the molecular mechanisms behind the defective immunomodulatory ability of mandibular BM-MSCs under the periodontitis settings. We found that mandibular BM-MSCs from P. gingivalis-induced periodontitis mice had significantly reduced expression of LncRNA SPIRE1 than that from normal control mice. LncRNA SPIRE1 knockdown in normal BM-MSCs caused Th17/Treg cell differentiation imbalance during the coculturing of BM-MSCs and CD4 T cells. In addition, LncRNA SPIRE1 was identified as a competitive endogenous RNA that sponges miR-181a-5p in BM-MSCs. Moreover, miR-181a-5p inhibition attenuated the impact of LncRNA SPIRE1 knockdown on the ability of BM-MSCs in modulating Th17/Treg balance. Prolactin receptor (PRLR) was validated as a downstream target of miR-181a-5p. Notably, targeted knockdown of LncRNA SPIRE1 or PRLR or transfection of miR-181a-5p mimics activated the JAK/STAT3 signaling in normal BM-MSCs, while treatment with STAT3 inhibitor C188-9 restored the immunomodulatory properties of periodontitis-associated BM-MSCs. Furthermore, BM-MSCs with miR-181a-5p inhibition or PRLR-overexpression showed enhanced in vivo immunosuppressive properties in the periodontitis mouse model. Our results indicate that the JAK/STAT3 pathway is involved in the immunoregulation of BM-MSCs, and provide critical insights into the development of novel targeted therapies against periodontitis.

LOC646762 Is Involved in Adipogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells

“…They play important regulatory roles in the differentiation of MSCs into adipocytes; however, few studies have explored the role of lncRNAs in adipogenic differentiation. 16 Our previous research study based on transcriptome sequencing confirmed that various lncRNAs regulate adipogenic differentiation in BMSCs. However, the regulation of adipogenic differentiation by lncRNA in BMSCs remains largely unexplored.…”

“…Among these, long-chain noncoding RNAs (lncRNAs) have received increasing attention due to their important regulatory roles. , LncRNAs are the most abundant type of noncoding RNA and comprise >200 nt long transcripts that play important roles in cell differentiation, growth, development, and onset of many diseases. , LncRNAs exhibit multiple regulatory functions and participate in several important biological processes. They play important regulatory roles in the differentiation of MSCs into adipocytes; however, few studies have explored the role of lncRNAs in adipogenic differentiation . Our previous research study based on transcriptome sequencing confirmed that various lncRNAs regulate adipogenic differentiation in BMSCs.…”

Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles

“…Whilst many of these RNAs may be circulating from a variety of sources and may also be present within non-cancer populations, combinations of these molecules specifically linked with bone remodeling may provide a potential means of monitoring pre-metastatic niche development. For example, SPIRE1 was found to be one of the most abundant of the RNAs analyzed and has known roles in immunomodulation of bone marrow mesenchymal stem cells ( Shao et al, 2023 ). Further research into this area may provide the potential to identify patients at risk of bone metastasis at the earliest stages.…”

Mg-Cross-Linked Alginate Hydrogel Induces BMSC/Macrophage Crosstalk to Enhance Bone Tissue Regeneration via Dual Promotion of the Ligand–Receptor Pairing of the OSM/miR-370-3p-gp130 Signaling Pathway

“…With their capacity for self-renewal and potent osteogenic differentiation capacities, bone marrow-derived mesenchymal stem cells (BMSCs) are regarded as an essential stem cell source for bone regeneration. , The fate determination of BMSCs was manipulated by a wide range of factors, especially immune factors. Accumulating evidence has indicated that various immune cells interact with BMSCs in the bone defect area and bone marrow cavity. , Recently, much attention has been focused on the crucial function of macrophages in the recruitment and differentiation of MSCs throughout the process of bone regeneration .…”