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MiRNA Let-7i-5p-Contained Small Extracellular Vesicles from Macrophages Induce Nucleus Pulposus Cell Senescence via

Shuo Zhang1,2, Miaoheng Yan3, Xiao Lv2

  • 1School of Medicine, Nankai University, Tianjin, 300071, People's Republic of China.

International Journal of Nanomedicine
|February 24, 2025
PubMed
Abstract

Insights

Macrophage-derived small extracellular vesicles (MΦ-sEVs) accelerate nucleus pulposus cell (NPC) senescence and intervertebral disc degeneration (IVDD). MΦ-sEVs deliver microRNA let-7i-5p, inhibiting LIN28A to promote senescence.

Area of Science:

  • Extracellular Vesicles Research
  • Cellular Senescence
  • Molecular Biology

Background:

  • Intervertebral disc degeneration (IVDD) is linked to nucleus pulposus (NP) cell senescence.
  • Macrophage-derived small extracellular vesicles (MΦ-sEVs) are implicated in inflammatory processes.
  • The specific role of MΦ-sEVs in NP cell senescence and IVDD remains unclear.

Purpose of the Study:

  • To investigate the role of MΦ-sEVs in nucleus pulposus (NP) cell (NPC) senescence.
  • To identify pro-senescence microRNAs (miRNAs) within MΦ-sEVs.
  • To explore potential mRNA targets of these miRNAs.

Main Methods:

  • Isolation and characterization of bone marrow-derived macrophage (BMDM)-derived sEVs.
  • Treatment of NPCs with MΦ-sEVs and assessment of senescence markers (SA-β-Gal, Western blotting).
  • In vivo studies in rat coccygeal NP tissues to evaluate MΦ-sEVs' effect on IVDD and NPC senescence.
  • miRNA profiling of MΦ-sEVs using PANDORA sequencing and functional screening in NPCs.

Main Results:

  • MΦ-sEVs, regardless of activation state (LPS+IFNγ or IL-4), impaired NPC viability and accelerated senescence.
  • MΦ-sEVs increased senescence-associated secretory phenotype (SASP) markers and senescence proteins (p16, p21, p53).
  • In vivo administration of MΦ-sEVs exacerbated IVDD, increased p16-positive cells, and activated SASP.
  • PANDORA sequencing identified let-7i-5p as a highly abundant miRNA in MΦ-sEVs, which induced senescence by downregulating LIN28A.

Conclusions:

  • Both activated and non-activated MΦ-sEVs induce NPC senescence.
  • MΦ-sEVs exacerbate intervertebral disc degeneration in vivo.
  • The mechanism involves MΦ-sEVs delivering let-7i-5p to inhibit LIN28A, thereby promoting NPC senescence.
Keywords:
intervertebral disc degenerationlet-7i-5pmacrophage-derived small extracellular vesiclenucleus pulposus cellsenescence

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