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Computational analysis identifies putative prognostic biomarkers of pathological scarring in skin wounds.

ABSTRACT: BACKGROUND:Pathological scarring in wounds is a prevalent clinical outcome with limited prognostic options. The objective of this study was to investigate whether cellular signaling proteins could be used as prognostic biomarkers of pathological scarring in traumatic skin wounds. METHODS:We used our previously developed and validated computational model of injury-initiated wound healing to simulate the time courses for platelets, 6 cell types, and 21 proteins involved in the inflammatory and proliferative phases of wound healing. Next, we analysed thousands of simulated wound-healing scenarios to identify those that resulted in pathological (i.e., excessive) scarring. Then, we identified candidate proteins that were elevated (or decreased) at the early stages of wound healing in those simulations and could therefore serve as predictive biomarkers of pathological scarring outcomes. Finally, we performed logistic regression analysis and calculated the area under the receiver operating characteristic curve to quantitatively assess the predictive accuracy of the model-identified putative biomarkers. RESULTS:We identified three proteins (interleukin-10, tissue inhibitor of matrix metalloproteinase-1, and fibronectin) whose levels were elevated in pathological scars as early as 2 weeks post-wounding and could predict a pathological scarring outcome occurring 40 days after wounding with 80% accuracy. CONCLUSION:Our method for predicting putative prognostic wound-outcome biomarkers may serve as an effective means to guide the identification of proteins predictive of pathological scarring.

SUBMITTER: Nagaraja S

PROVIDER: S-EPMC5819197 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Computational analysis identifies putative prognostic biomarkers of pathological scarring in skin wounds.

Nagaraja Sridevi S Chen Lin L DiPietro Luisa A LA Reifman Jaques J Mitrophanov Alexander Y AY

Journal of translational medicine 20180220 1

<h4>Background</h4>Pathological scarring in wounds is a prevalent clinical outcome with limited prognostic options. The objective of this study was to investigate whether cellular signaling proteins could be used as prognostic biomarkers of pathological scarring in traumatic skin wounds.<h4>Methods</h4>We used our previously developed and validated computational model of injury-initiated wound healing to simulate the time courses for platelets, 6 cell types, and 21 proteins involved in the infla ...[more]

PMID: 29458433

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Project description:BackgroundThe high incidence of pre-eclampsia, which affects 2-7% of all pregnancies, remains a major health concern. Detection of pre-eclampsia before the appearance of clinical symptoms is essential to allow early intervention, and would benefit from identification of plasma/serum biomarkers to help guide diagnosis and treatment. Liquid biopsy has emerged as a promising source of protein biomarkers that circumvents some of the inherent challenges of proteome-wide analysis of plasma/serum. In this respect, purified exosomes have the added benefit of being carriers of intercellular communication both in physiological and pathological conditions.MethodsWe compared the protein complement of purified exosomes from three different collections of control and pre-eclamptic serum samples, obtained at the end of the second trimester of pregnancy and at delivery. We employed shotgun label-free proteomics to investigate differential protein expression, which was then validated by targeted proteomics.ResultsWe developed a purification method that yielded highly enriched exosome preparations. The presence of specific pregnancy protein markers suggested that a significant proportion of purified exosomes derived from tissues related to pregnancy. Quantitative proteomic analyses allowed us to identify 10, 114 and 98 differentially-regulated proteins in the three sample collections, with a high degree of concordance. Functional analysis suggested that these proteins participate in biological processes related to pre-eclampsia, including angiogenesis, inflammation and cell migration. The differential abundance of 66 proteins was validated by targeted proteomics. Finally, we studied the impact of the pre-eclampsia-associated exosomes in the proteome using an in vitro cellular model.ConclusionsWe have identified and validated differential exosomal proteins in liquid biopsy of pregnant women that open new possibilities for early detection of pre-eclampsia. Additionally, the functional impact of the proteome composition of purified pre-eclamptic exosomes in target cells provides new information to better understand changes in embryo-maternal interactions and, consequently, the pathogenesis of this disease.

Project description:Hypertrophic and atrophic scars are the effect of a dysregulated wound-healing process in genetically predisposed individuals. The genetic predisposition has acquired significant attention due to the diverse phenotype of pathological scarring in individuals with a positive personal and family history. Recent studies have identified telomere shortening and decreased hTERT activity in pathological scarring, proposing the rs2736100 variant of human telomerase reverse transcriptase (hTERT) gene as a valuable variant gene candidate. We examined the scarring process in 71 female patients who had undergone Caesarean section and developed hypertrophic and atrophic scars with the objective to investigate the role of single nucleotide polymorphism (SNP) rs2736100 in pathological scarring. Genotyping was performed using RT-PCR and follow-up included the Patient Observer Scar Assessment Scale (POSAS) and SCAR scales. Comparative analysis for mean POSAS value between the check-ups at 3 and 6 months revealed a statistical decreased difference of 1.71 points [95% confidence interval (CI), 0.4-2.89; P=0.01], while SCAR highlighted a decreased difference of 0.670 (95% CI, -0.04-1.38; P=0.055). The C variant allele revealed a borderline statistical value for the risk of developing pathological scarring (OR=1.44; 95% CI, 0.876-1.332: P=0.066). In our study a pre-conceptional body mass index (BMI) >25 kg/m2 was statistically associated with pathological scarring. The Fitzpatrick type 4 phototype displayed an increased frequency for the heterozygous genotype in the current study, and it was demonstrated that dark skin tone was associated with abnormal scar formation. Our study investigated the role of hTERT gene variant rs2736100 in hypertrophic and atrophic scarring in a Caucasian population group. We report a borderline statistically significant value for the variant C allele of hTERT SNP for the risk of developing pathological scarring in female patients that had undergone Caesarean section.

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Computational analysis identifies putative prognostic biomarkers of pathological scarring in skin wounds.

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Computational analysis identifies putative prognostic biomarkers of pathological scarring in skin wounds.

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