JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models

Borrelli, Mimi R.; Garcia, Julia T.; Januszyk, Michael; King, Megan E.; Lerbs, Tristan; Moore, Alessandra L.; Shen, Abra H.; Mascharak, Shamik; Deleon, Nestor M. Diaz; Adem, Sandeep; Taylor, Walter L.; desJardins-Park, Heather E.; Gastou, Marc; Patel, Ronak A.; Duoto, Bryan; Sokol, Jan; Wei, Yuning; Foster, Deshka S.; Chen, Kellen; Wan, Derrick C.; Gurtner, Geoffrey C.; Lorenz, H. Peter; Chang, Howard Y.; Wernig, Gerlinde; Longaker, Michael T.

doi:10.1126/scitranslmed.abb3312

Cited by 33 publications

(21 citation statements)

References 69 publications

(82 reference statements)

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“…Previous studies have reported homozygous Jund −/− mutant male mice showed defective spermatogenesis and decreased fertility, and the knockout of c-Fos also blocked normal spermatogenesis [ 48 , 49 ]. JUN is an important component of the AP-1 complex, which is known for transcription activation, and also plays essentials roles in different biological processes, including the development of heart and liver, tissue scarring and others [ 50 – 52 ]. In fact, Jun −/− mice have demonstrated arrested embryonic development at E13 due to the failure of organ development [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

PA1 participates in the maintenance of blood–testis barrier integrity via cooperation with JUN in the Sertoli cells of mice

Liu

et al. 2022

Cell Biosci

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Background The blood–testis barrier (BTB) is essential to the microenvironment of spermatogenesis, and Sertoli cells provide the cellular basis for BTB construction. Numerous nuclear transcription factors have been identified to be vital for the proper functioning of Sertoli cells. PA1 has been reported to play important roles during diverse biological processes, yet its potential function in male reproduction is still unknown. Results Here, we show that PA1 was highly expressed in human and mouse testis and predominantly localized in the nuclei of Sertoli cells. Sertoli cell-specific Pa1 knockout resulted in an azoospermia-like phenotype in mice. The knockout of this gene led to multiple defects in spermatogenesis, such as the disorganization of the cytoskeleton during basal and apical ectoplasmic specialization and the disruption of the BTB. Further transcriptomic analysis, together with Cut-Tag results of PA1 in Sertoli cells, revealed that PA1 could affect the expression of a subset of genes that are essential for the normal function of Sertoli cells, including those genes associated with actin organization and cellular junctions such as Connexin43 (Cx43). We further demonstrated that the expression of Cx43 depended on the interaction between JUN, one of the AP-1 complex transcription factors, and PA1. Conclusion Overall, our findings reveal that PA1 is essential for the maintenance of BTB integrity in Sertoli cells and regulates BTB construction-related gene expression via transcription factors. Thus, this newly discovered mechanism in Sertoli cells provides a potential diagnostic or even therapeutic target for some individuals with azoospermia.

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Section: Discussionmentioning

confidence: 99%

PA1 participates in the maintenance of blood–testis barrier integrity via cooperation with JUN in the Sertoli cells of mice

Liu

et al. 2022

Cell Biosci

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“…Additionally, administration with the nuclear Yap-TEAD inhibitor verteporfin prolonged myofibroblast persistence and converted tissue regeneration to fibrosis in vivo [ 69 ]. JUN initiates hypertrophic scar formation by regulating CD36, modulating distinct fibroblast subpopulations, boosting reticular fibroblasts, and decreasing levels of lipofibroblasts [ 70 ].…”

Section: Regulation Of Fibroblasts In Wound Healing and Scar Formationmentioning

confidence: 99%

Fibroblasts in Scar Formation: Biology and Clinical Translation

Qian

Shan

Gong

et al. 2022

Oxidative Medicine and Cellular Longevity

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Scarring, which develops due to fibroblast activation and excessive extracellular matrix deposition, can cause physical, psychological, and cosmetic problems. Fibroblasts are the main type of connective tissue cells and play important roles in wound healing. However, the underlying mechanisms of fibroblast in reaching scarless wound healing require more exploration. Herein, we systematically reviewed how fibroblasts behave in response to skin injuries, as well as their functions in regeneration and scar formation. Several biocompatible materials, including hydrogels and nanoparticles, were also suggested. Moreover, factors that concern transformation from fibroblasts into cancer-associated fibroblasts are mentioned due to a tight association between scar formation and primary skin cancers. These findings will help us better understand skin fibrotic pathogenesis, as well as provide potential targets for scarless wound healing therapies.

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“…The FB-1 in HS had a higher expression level of TWIST2 than that in NS ( Figure 7B , adjusted p -value < 0.05). The previous study identified JUN as a critical regulator by promoting hypertrophic skin scarring ( Griffin et al, 2021 ). Consistently, we also found that the transcriptional activity of JUN was higher in HS than NS ( Supplementary Figure S1 ).…”

Section: Resultsmentioning

confidence: 99%

Single-Cell and Bulk Transcriptome Data Integration Reveals Dysfunctional Cell Types and Aberrantly Expressed Genes in Hypertrophic Scar

Zhang

Min

2022

Front. Genet.

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Hypertrophic scar (HS) is a common skin disorder characterized by excessive extracellular matrix (ECM) deposition. However, it is still unclear how the cellular composition, cell-cell communications, and crucial transcriptionally regulatory network were changed in HS. In the present study, we found that FB-1, which was identified a major type of fibroblast and had the characteristics of myofibroblast, was significantly expanded in HS by integrative analysis of the single-cell and bulk RNA sequencing (RNA-seq) data. Moreover, the proportion of KC-2, which might be a differentiated type of keratinocyte (KC), was reduced in HS. To decipher the intercellular signaling, we conducted the cell-cell communication analysis between the cell types, and found the autocrine signaling of HB-1 through COL1A1/2-CD44 and CD99-CD99 and the intercellular contacts between FB-1/FB-5 and KC-2 through COL1A1/COL1A2/COL6A1/COL6A2-SDC4. Almost all the ligands and receptors involved in the autocrine signaling of HB-1 were upregulated in HS by both scRNA-seq and bulk RNA-seq data. In contrast, the receptor of KC-2, SDC4, which could bind to multiple ligands, was downregulated in HS, suggesting that the reduced proportion of KC-2 and apoptotic phenotype of KC-2 might be associated with the downregulation of SDC4. Furthermore, we also investigated the transcriptionally regulatory network involved in HS formation. The integrative analysis of the scRNA-seq and bulk RNA-seq data identified CREB3L1 and TWIST2 as the critical TFs involved in the myofibroblast of HS. In summary, the integrative analysis of the single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data greatly improved our understanding of the biological characteristics during the HS formation.

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JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models

Abstract: JUN drives scarring by modifying the roles of fibroblast subpopulations, and JUN antagonism via CD36 may represent an antiscarring therapy.

Cited by 33 publications

References 69 publications

PA1 participates in the maintenance of blood–testis barrier integrity via cooperation with JUN in the Sertoli cells of mice

PA1 participates in the maintenance of blood–testis barrier integrity via cooperation with JUN in the Sertoli cells of mice

Fibroblasts in Scar Formation: Biology and Clinical Translation

Single-Cell and Bulk Transcriptome Data Integration Reveals Dysfunctional Cell Types and Aberrantly Expressed Genes in Hypertrophic Scar

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