Omics · study · 2026
Macrophage-derived CCL13 drives uterine fibrosis via SIX1-SPP1 signaling in CCR1-expressing fibroblasts [scRNA-seq]
Listed in NCBI GEO
Uterine scarring (US), a prevalent sequela of cesarean sections and uterine surgeries, significantly impairs reproductive outcomes.
Description
However, cellular and molecular mechanisms driving US remain elusive. Through single-cell RNA sequencing of human myometrial tissues, we identified pathological expansions of secreted phosphoprotein 1-positive (SPP1+) fibroblasts and M2-like apolipoprotein E-expressing (APOE+) (MAC-APOE) macrophages in US.
CellChat analysis and functional assays revealed a paracrine C-C Motif Chemokine Ligand 13 (CCL13) - C-C motif chemokine receptor 1 (CCR1) axis: MAC-APOE macrophage-derived CCL13 activates CCR1 on SPP1+ fibroblasts, driving fibroblast activation and fibrogenesis. Fibroblast-specific CCR1 overexpression in mice exacerbated uterine fibrosis, establishing a causal role of CCR1 in US pathogenesis. Critically, elevated plasma CCL13/CCR1 levels in normal/US pregnancies positively correlated with the severity of human uterine fibrosis, suggesting a strong association between CCR1 and uterine scar fibrosis.
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Mechanistically, CCR1 signaling induces Six homeobox 1 (SIX1) phosphorylation and nuclear translocation, directly stimulating Spp1 ranscription. Subsequent Coat Protein Complex II (COPII) vesicle-dependent osteopontin (OPN, encoded by the Spp1 gene) secretion amplifies fibroblast-to-myofibroblast transition and fibrosis. Translationally, we engineered Ccr1-targeting siRNA lipid nanoparticles (LNP/siCcr1) for spatially controlled delivery via local administration or hydrogel-based (PLNP/siCcr1) sustained release.
This strategy attenuated uterine fibrosis, improved pregnancy rates, and reduced embryo resorption in murine models. Meanwhile, long-term safety evaluation of PLNP/siCcr1 in uterine tissues of non-pregnant female mice confirmed that PLNP/siCcr1 was well-tolerated and caused no reproductive toxicity after these treated female mice were mated. Collectively, our work defines a macrophage-fibroblast signaling circuit driving uterine fibrosis and nominates CCR1 as a potential therapeutic target for preventing US-associated fibrotic complications.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE337nnn/GSE337145 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE337145 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1481804 ncbi.nlm.nih.gov/bioproject/PRJNA1481804 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- RNA sequencing 75% · Sequencing 75% · Single-cell RNA sequencing 75%
Provenance · 1 source records, 10 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE337145 | 13 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[modality].local:modality:sequencing | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[modality].local:modality:single-cell-rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |