Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity

Cui, Lü; Chen, Shih‐Yu; Lerbs, Tristan; Lee, Jin Wook; Domizi, Pablo; Gordon, Sydney R.; Kim, Yong‐hun; Nolan, Garry P.; Betancur, Paola; Wernig, Gerlinde

doi:10.1038/s41467-020-16466-4

Cited by 82 publications

(84 citation statements)

References 58 publications

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“…Fibrosis is marked by an excessive amount of connective tissue primarily formed by fibroblasts. One of the genes that fibroblasts commonly upregulate in several fibrotic conditions, especially idiopathic pulmonary fibrosis, is the transcription factor JUN, as our group has recently shown (6,7). JUN, which belongs to the family of the AP-1 transcription factors and is activated through phosphorylation (phosphorylated JUN, p-JUN), otherwise contributes to malignant diseases and plays a role in different developmental programs (8,9).…”

Section: Introductionmentioning

confidence: 99%

CD47 prevents the elimination of diseased fibroblasts in scleroderma

Lerbs¹,

King²,

Chai

et al. 2020

JCI Insight

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Section: Introductionmentioning

confidence: 99%

CD47 prevents the elimination of diseased fibroblasts in scleroderma

Lerbs¹,

King²,

Chai

et al. 2020

JCI Insight

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“…The final group, subcluster 3 , demonstrated differential activation of JUN , FOS , and ACTA2 . These cells likely represent a human analog to the pro-fibrotic subpopulation of cells that has been previously described by our group and others [ 45 ]. Furthermore, these data suggest that a small subpopulation of cells highly expressing EN1 may specifically drive the transcriptional shift into this pro-fibrotic state.…”

Section: Resultsmentioning

confidence: 90%

Characterization of Diabetic and Non-Diabetic Foot Ulcers Using Single-Cell RNA-Sequencing

et al. 2020

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Background: Recent advances in high-throughput single-cell sequencing technologies have led to their increasingly widespread adoption for clinical applications. However, challenges associated with tissue viability, cell yield, and delayed time-to-capture have created unique obstacles for data processing. Chronic wounds, in particular, represent some of the most difficult target specimens, due to the significant amount of fibrinous debris, extracellular matrix components, and non-viable cells inherent in tissue routinely obtained from debridement. Methods: Here, we examined the feasibility of single cell RNA sequencing (scRNA-seq) analysis to evaluate human chronic wound samples acquired in the clinic, subjected to prolonged cold ischemia time, and processed without FACS sorting. Wound tissue from human diabetic and non-diabetic plantar foot ulcers were evaluated using an optimized 10X Genomics scRNA-seq platform and analyzed using a modified data pipeline designed for low-yield specimens. Cell subtypes were identified informatically and their distributions and transcriptional programs were compared between diabetic and non-diabetic tissue. Results: 139,000 diabetic and non-diabetic wound cells were delivered for 10X capture after either 90 or 180 min of cold ischemia time. cDNA library concentrations were 858.7 and 364.7 pg/µL, respectively, prior to sequencing. Among all barcoded fragments, we found that 83.5% successfully aligned to the human transcriptome and 68% met the minimum cell viability threshold. The average mitochondrial mRNA fraction was 8.5% for diabetic cells and 6.6% for non-diabetic cells, correlating with differences in cold ischemia time. A total of 384 individual cells were of sufficient quality for subsequent analyses; from this cell pool, we identified transcriptionally-distinct cell clusters whose gene expression profiles corresponded to fibroblasts, keratinocytes, neutrophils, monocytes, and endothelial cells. Fibroblast subpopulations with differing fibrotic potentials were identified, and their distributions were found to be altered in diabetic vs. non-diabetic cells. Conclusions: scRNA-seq of clinical wound samples can be achieved using minor modifications to standard processing protocols and data analysis methods. This simple approach can capture widespread transcriptional differences between diabetic and non-diabetic tissue obtained from matched wound locations.

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“…In detail they speculated one reason of CD47 up-regulation may be the participation of inflammatory cytokines TNF-α, CXCL10, and IFN-α [ 94 ]. Specifically in fibrotic associated fibroblast, JUN was worked as an enhancer to CD47 [ 95 ]. Moreover, valid data had proved CD47 up-regulation on vascular smooth muscle cells was cause by TNF-α, probably explained why there is an impairment in macrophage phagocytosis within human atherosclerotic plaque [ 96 ].…”

Section: Discussionmentioning

confidence: 99%

Regulation of CD47 expression in cancer cells

Huang

et al. 2020

Translational Oncology

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CD47 is overexpressed in various types of cancers and it can directly bind with SIRPα, which is mainly located on macrophages. The binding of CD47-SIRPα transmits a “don't eat me” signal, which can prevent cancer cells from immune clearance. Targeting the phagocytosis checkpoint of CD47-SIRPα axis has shown remarkable anticancer effect in preclinical and clinical research, which indicates the potential application of CD47-SIRPα blockade for cancer treatment. In this case, the comprehensive description of the regulation of CD47 in different types of cancer cells has significant implications for furthering our understanding of the role of CD47 in cancer. Based on the current reports, we summarized the regulatory factors, i.e. , cytokines, oncogenes, microRNAs as well as enzymes, of CD47 expression in cancer cells. Accordingly, we also proposed several points needing further research, hoping to provide useful insights for the future investigation on the regulation of CD47 in cancers.

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Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity

Cited by 82 publications

References 58 publications

CD47 prevents the elimination of diseased fibroblasts in scleroderma

CD47 prevents the elimination of diseased fibroblasts in scleroderma

Characterization of Diabetic and Non-Diabetic Foot Ulcers Using Single-Cell RNA-Sequencing

Regulation of CD47 expression in cancer cells

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