Novel proteins that regulate cell extension formation in fibroblasts

Yuda, Atsushi; Ws, Lee; Petrovic, Petar; McCulloch, CA

doi:10.1016/j.yexcr.2018.02.024

Cited by 8 publications

(5 citation statements)

References 38 publications

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“…As a member of the PDZ-LIM family, PDLIM5 was clearly shown to be an actin skeleton-related protein. It plays an indispensable role in the functional activity of cell biology [27,39]. In the present study, knocking down PDLIM5 significantly inhibited the proliferation, movement, and migration of fibroblasts, suggesting that PDLIM5 participates in the biological function of HSFs.…”

Section: Discussionsupporting

confidence: 59%

“…By modulating BMP2-Smad signaling and the expression of this signaling downstream target gene RUNX2 by regulating the aggregation state of microfilaments, thus affect osteoblastic differentiation of osteoblasts [35,36]. It is known that PDLIM5 plays an important role in cardiovascular system [37], nervous system [38], and tumor system [39]. However, its role in fibroblasts has not been specifically elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Mechanical Sensing Element PDLIM5 Promotes Osteogenesis of Human Fibroblasts by Affecting the Activity of Microfilaments

Huang

Peng

et al. 2021

Biomolecules

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Human skin fibroblasts (HSFs) approximate the multidirectional differentiation potential of mesenchymal stem cells, so they are often used in differentiation, cell cultures, and injury repair. They are an important seed source in the field of bone tissue engineering. However, there are a few studies describing the mechanism of osteogenic differentiation of HSFs. Here, osteogenic induction medium was used to induce fibroblasts to differentiate into osteoblasts, and the role of the mechanical sensitive element PDLIM5 in microfilament-mediated osteogenic differentiation of human fibroblasts was evaluated. The depolymerization of microfilaments inhibited the expression of osteogenesis-related proteins and alkaline phosphatase activity of HSFs, while the polymerization of microfilaments enhanced the osteogenic differentiation of HSFs. The evaluation of potential protein molecules affecting changes in microfilaments showed that during the osteogenic differentiation of HSFs, the expression of PDLIM5 increased with increasing induction time, and decreased under the state of microfilament depolymerization. Lentivirus-mediated PDLIM5 knockdown by shRNA weakened the osteogenic differentiation ability of HSFs and inhibited the expression and morphological changes of microfilament protein. The inhibitory effect of knocking down PDLIM5 on HSF osteogenic differentiation was reversed by a microfilament stabilizer. Taken together, these data suggest that PDLIM5 can mediate the osteogenic differentiation of fibroblasts by affecting the formation and polymerization of microfilaments.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Mechanical Sensing Element PDLIM5 Promotes Osteogenesis of Human Fibroblasts by Affecting the Activity of Microfilaments

Huang

Peng

et al. 2021

Biomolecules

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“…Surprisingly, collagen type I amount is dramatically increased with Cmp 2 at 25 µM (22 µg/mL) with respect to the DMSO control (14.8 µg/mL) and compared to Meloxicam and Cmp 7. In that experimental condition, microscopic observations reveal the presence of a network of flattened cell extensions between adjacent cells which have been proven to be critical structures that enable matrix remodeling in fibroblasts secreting collagen fibers [29] (Figure 6B). Being less efficient as regards the CO releasing profile compared to that of Cmp 7 [17] and in counteracting H 2 O 2 -related cytotoxicity, Cmp 2 is instead extremely active in increasing collagen type I secretion, as if tenocytes were in a different stage of the healing.…”

Section: Compound 2 Enhances Collagen Type I Secretion In H 2 O 2 -Stimulated Tenocytesmentioning

confidence: 85%

Dual Acting Carbon Monoxide Releasing Molecules and Carbonic Anhydrase Inhibitors Differentially Modulate Inflammation in Human Tenocytes

et al. 2021

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Sustained oxidative stress and inflammation have been reported as the major factors responsible for the failure of tendon healing during rotator cuff tears (RCTs) and rotator cuff disease (RCD). Although, their therapeutic management remains still challenging. Carbonic anhydrases (CAs) are involved in many pathological conditions, and the overexpression of both CA9 and 12 in inflamed joints has been recently reported. Consequently, a selective CA9/12 inhibition could be a feasible strategy for improving tendon recovery after injury. In addition, since carbon monoxide (CO) has been proven to have an important role in modulating inflammation, CO releasing molecules (CORMs) can be also potentially suitable compounds. The present study aims at evaluating five newly synthesized dual-mode acting CA inhibitors (CAIs)-CORMs compounds, belonging to two chemical scaffolds, on tendon-derived human primary cells under H2O2 stimulation in comparison with Meloxicam. Our results show that compounds 2 and 7 are the most promising of the series in counteracting oxidative stress-induced cytotoxicity and display a better profile in terms of enhanced viability, decreased LDH release, and augmented tenocyte proliferation compared to Meloxicam. Moreover, compound 7, as a potent superoxide scavenger, exerts its action inhibiting NF-ĸB translocation and downregulating iNOS, whereas compound 2 is more effective in increasing collagen I deposition. Taken together, our data highlight a potential role of CA in RCTs and RCD and the prospective effectiveness of compounds acting as CAI-CORM during inflammation.

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“…PSMC4 gene, traditionally known to be part of the 26S proteasome and involved in the maintenance of protein homeostasis by removing misfolded or damaged proteins, has more recently proven itself to be involved in many different modulated pathways, including cell extension formation in fibroblast enabling matrix remodelling 46 and cell proliferation and tumorigenesis 47 . Assuming that hypersegmentation is associated with a shift in the cellular machinery of neutrophils leading to certain proteins becoming redundant or damaged, and based on PSMC4's function, we can speculate that its upregulation may be involved in the removal of misfolded, damaged, or no longer used proteins, but this has not yet been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Characterising the transcriptome of hypersegmented human neutrophils

Fox¹,

Jones²,

Samanta³

et al. 2021

Wellcome Open Res

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Background: Mature human neutrophils are characterised by their multilobed nuclear morphology. Neutrophil hypersegmentation, a pathologic nuclear phenotype, has been described in the alveolar compartment of patients with acute respiratory distress syndrome and in several other contexts. This study aimed to characterise the transcriptional changes associated with neutrophil hypersegmentation. Methods: A model of hypersegmentation was established by exposing healthy peripheral blood neutrophils to the angiotensin converting enzyme inhibitor (ACEi) captopril. Laser capture microdissection (LCM) was then adapted to isolate a population of hypersegmented neutrophils. Transcriptomic analysis of microdissected hypersegmented neutrophils was undertaken using ribonucleic acid (RNA) sequencing. Differential gene expression (DEG) and enrichment pathway analysis were conducted to investigate the mechanisms underlying hypersegmentation. Results: RNA-Seq analysis revealed the transcriptomic signature of hypersegmented neutrophils, with five genes differentially expressed. VCAN, PADI4 and DUSP4 were downregulated, while LTF and PSMC4 were upregulated. Modulated pathways included histone modification, protein-DNA complex assembly and antimicrobial humoral response. The role of PADI4 was further validated using the small molecule inhibitor, Cl-amidine. Conclusions: Hypersegmented neutrophils display a marked transcriptomic signature, characterised by the differential expression of five genes. This study provides insights into the mechanisms underlying neutrophil hypersegmentation and describes a novel method to isolate and sequence neutrophils based on their morphologic subtype.

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Novel proteins that regulate cell extension formation in fibroblasts

Cited by 8 publications

References 38 publications

Mechanical Sensing Element PDLIM5 Promotes Osteogenesis of Human Fibroblasts by Affecting the Activity of Microfilaments

Mechanical Sensing Element PDLIM5 Promotes Osteogenesis of Human Fibroblasts by Affecting the Activity of Microfilaments

Dual Acting Carbon Monoxide Releasing Molecules and Carbonic Anhydrase Inhibitors Differentially Modulate Inflammation in Human Tenocytes

Characterising the transcriptome of hypersegmented human neutrophils

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