Cited by 16Liver physiology and pathologyLiver Disease Diagnosis and TreatmentLiver Diseases and Immunity

Multiplexed Digital Spatial Protein Profiling Reveals Distinct Phenotypes of Mononuclear Phagocytes in Livers with Advanced Fibrosis

Open access
Lee, Jaejun, Kim, Chang Min, Cha, Jung Hoon, Park, Jin Young, Yu, Yun Suk, Wang, Hee Jung, Sung, Pil Soo, Jung, Eun Sun +1 more·2022·Cells

Abstract

Background and Aims: Intrahepatic mononuclear phagocytes (MPs) are critical for the initiation and progression of liver fibrosis. In this study, using multiplexed digital spatial protein profiling, we aimed to derive a unique protein signature predicting advanced liver fibrosis. Methods: Snap-frozen liver tissues from various chronic liver diseases were subjected to spatially defined protein-based multiplexed profiling (Nanostring GeoMXTM). A single-cell RNA sequencing analysis was performed using Gene Expression Omnibus (GEO) datasets from normal and cirrhotic livers. Results: Sixty-four portal regions of interest (ROIs) were selected for the spatial profiling. Using the results from the CD68+ area, a highly sensitive and specific immune-related protein signature (CD68, HLA-DR, OX40L, phospho-c-RAF, STING, and TIM3) was developed to predict advanced (F3 and F4) fibrosis. A combined analysis of single-cell RNA sequencing data from GEO datasets (GSE136103) and spatially-defined, protein-based multiplexed profiling revealed that most proteins upregulated in F0–F2 livers in portal CD68+ cells were specifically marked in tissue monocytes, whereas proteins upregulated in F3 and F4 livers were marked in scar-associated macrophages (SAMacs) and tissue monocytes. Internal validation using mRNA expression data with the same cohort tissues demonstrated that mRNA levels for TREM2, CD9, and CD68 are significantly higher in livers with advanced fibrosis. Conclusions: In patients with advanced liver fibrosis, portal MPs comprise of heterogeneous populations composed of SAMacs, Kupffer cells, and tissue monocytes. This is the first study that used spatially defined protein-based multiplexed profiling, and we have demonstrated the critical difference in the phenotypes of portal MPs between livers with early- or late-stage fibrosis.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/cells11213387

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Lee, J., Kim, C. M., Cha, J. H., Park, J. Y., Yu, Y. S., Wang, H. J., Sung, P. S., Jung, E. S., & Bae, S. H.
Affiliations
  • Republic of Korea Army (KR)
  • CbsBioscience, Inc., Daejeon 34036, Korea
  • The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
  • Inje University Haeundae Paik Hospital (KR)
  • The Catholic University of Korea Seoul St. Mary's Hospital (KR)
  • The Catholic University of Korea Eunpyeong St. Mary's Hospital (KR)
Corresponding author
  • Sung, Pil Soo
  • Jung, Eun Sun
  • Bae, Si Hyun
Venue
Cells
Publisher
MDPI AG
Published
2022-10-26
Volume
11
Issue
21
Pages
3387
ISSN
2073-4409 (ISSN-L)
OpenAlex
W4307553129
Cited by
16
References
45
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 6
FWCI
2.09
Type
journal article
Language
en
Open access
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Korean government (MSIT) (2020R1A2C3011569)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
liver fibrosis, mononuclear phagocytes, Kupffer cells, CD68, proteomic signatures, fibrosis prediction, NanoString GeoMx, single-cell RNA sequencing, TREM2, CD9, chronic liver disease
MeSH terms
Humans, Kupffer Cells, Liver Cirrhosis, Phenotype, RNA, Messenger

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review