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PreprintCited by 19Tendon Structure and TreatmentWound Healing and TreatmentsPeriodontal Regeneration and Treatments

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eEF2 improves dense connective tissue repair and healing outcome by regulating cellular death, autophagy, apoptosis, proliferation and migration

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Chen, Junyu, Wang, Jin, Wu, Xinjie, Simon, Nils, Svensson, Camilla I, Yuan, Juan, Hart, David A, Ahmed, Aisha S, Ackermann, Paul W·2023·Cellular and Molecular Life Sciences
DOI 10.21203/rs.3.rs-2424611/v1PMC PMC10121543

Preprint — published as 10.1007/s00018-023-04776-x

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Abstract

Outcomes following human dense connective tissue (DCT) repair are often variable and suboptimal, resulting in compromised function and development of chronic painful degenerative diseases. Moreover, biomarkers and mechanisms that guide good clinical outcomes after DCT injuries are mostly unknown. Here, we characterize the proteomic landscape of DCT repair following human tendon rupture and its association with long-term patient-reported outcome. Moreover, the regulatory mechanisms of relevant biomarkers were assessed partly by gene silencing experiments. A Mass-Spectrometry based proteomic approach quantified a large number (769) of proteins, including 51 differentially expressed proteins among 20 good versus 20 poor outcome patients. A novel biomarker, elongation factor-2 (eEF2) was identified as being strongly prognostic of the 1-year clinical outcome. Further bioinformatic and experimental investigation revealed that eEF2 positively regulated autophagy, cell proliferation and migration, as well as reduced cell death and apoptosis, leading to improved DCT repair and outcomes. Findings of eEF2 as novel prognostic biomarker could pave the way for new targeted treatments to improve healing outcomes after DCT injuries.

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Fig. 1 Quantitative proteomic file of injured human Achilles tendon. a Volcano diagram with differentially expressed proteins. The X coordinate represents Log2 fold change (FC) and the Y coordinate to −Log10 (p-value). Each dot represents a protein with red = upregulated, green = downregulated and, black = non-differentially expressed proteins. b Bar plot of differentially expressed proteins with matched biological processes. The length of the bar represents the percentage of proteins which are enriched in each pathway; −log10 FDR was used as reliability, red = upregulated while green = downregulated proteins; The enrichment factor displays the ratio of the pathway related proteins in relation to the whole identified proteome. c Venn plot of overlapping and distinct proteomes of patients with good (G) and poor (P) outcome. n = 20 in each group; Protein–protein interactions among d upregulated and e downregulated proteins. STRING v11.0 was used to analyze functional enrichment. Relevant biological processes are presented with different colors; f–k GSEA plots of the highly involved pathways related to differentially expressed proteins
Fig. 1 Quantitative proteomic file of injured human Achilles tendon. a Volcano diagram with differentially expressed proteins. The X coordinate represents Log2 fold change (FC) and the Y coordinate to −Log10 (p-value). Each dot represents a protein with red = upregulated, green = downregulated and, black = non-differentially expressed proteins. b Bar plot of differentially expressed proteins with matched biological processes. The length of the bar represents the percentage of proteins which are enriched in each pathway; −log10 FDR was used as reliability, red = upregulated while green = downregulated proteins; The enrichment factor displays the ratio of the pathway related proteins in relation to the whole identified proteome. c Venn plot of overlapping and distinct proteomes of patients with good (G) and poor (P) outcome. n = 20 in each group; Protein–protein interactions among d upregulated and e downregulated proteins. STRING v11.0 was used to analyze functional enrichment. Relevant biological processes are presented with different colors; f–k GSEA plots of the highly involved pathways related to differentially expressed proteinsCC BY · PubMed Central
Fig. 2 Prognostic biomarker selection and verification in injured Achilles tendon tissues. Association of eEF2 expression with a ATRS and, b average heal rise, n = 40; c eEF2 expression between good outcome (GO, n = 20) and poor outcome (PO, n = 20) patients, data presented as mean ± SD, ***p < 0.001; Association among FBN2 and d ATRS and, e average heal rise, n = 40; f FBN2 levels among good outcome (GO, n = 20) and poor outcome (PO, n = 20) patients, data presented as mean ± SD, ***p < 0.001; g AUC for eEF2 to report its predictive significance, n = 40; h Semi-quantitative analysis of eEF2 western blot analysis among good outcome (GO, n = 9) and poor outcome (PO, n = 9) patient samples, data presented as mean ± SD, **p < 0.01, n = 9 per group; i Positive association between eEF2 and 1-year healing outcome based on western blot analysis, n = 18; j Western blot image of eEF2 and beta-actin (β-actin) in good (G) and poor (P) outcome patients
Fig. 2 Prognostic biomarker selection and verification in injured Achilles tendon tissues. Association of eEF2 expression with a ATRS and, b average heal rise, n = 40; c eEF2 expression between good outcome (GO, n = 20) and poor outcome (PO, n = 20) patients, data presented as mean ± SD, ***p < 0.001; Association among FBN2 and d ATRS and, e average heal rise, n = 40; f FBN2 levels among good outcome (GO, n = 20) and poor outcome (PO, n = 20) patients, data presented as mean ± SD, ***p < 0.001; g AUC for eEF2 to report its predictive significance, n = 40; h Semi-quantitative analysis of eEF2 western blot analysis among good outcome (GO, n = 9) and poor outcome (PO, n = 9) patient samples, data presented as mean ± SD, **p < 0.01, n = 9 per group; i Positive association between eEF2 and 1-year healing outcome based on western blot analysis, n = 18; j Western blot image of eEF2 and beta-actin (β-actin) in good (G) and poor (P) outcome patientsCC BY · PubMed Central
Fig. 3 eEF2 expression and localization in tissue biopsies and association with Col1a1. Immunohistochemistry of the eEF2 in a good outcome (GO) and, b poor outcome (PO) patients, Scale bars = 100 µm; c semi-quantitative analysis of eEF2 expression in the good outcome (GO) and poor outcome (PO) patient samples presented as integrated optical density (IOD), data reported as mean ± SD, ***p < 0.001, n = 9 per group. eEF2 immunofluorescence signal in a d good outcome (GO) and, e poor outcome (PO) patient sample. Scale bars = 100 µm; f Western blot analysis and g semi-quantitative analysis of Col1a1 expression in good and poor outcome patients. Signal intensity was used for quantitative analysis, and the intensity of the house-keeping gene (beta-actin) used for normalization; h association among eEF2 and Col1a1 expression, n = 18
Fig. 3 eEF2 expression and localization in tissue biopsies and association with Col1a1. Immunohistochemistry of the eEF2 in a good outcome (GO) and, b poor outcome (PO) patients, Scale bars = 100 µm; c semi-quantitative analysis of eEF2 expression in the good outcome (GO) and poor outcome (PO) patient samples presented as integrated optical density (IOD), data reported as mean ± SD, ***p < 0.001, n = 9 per group. eEF2 immunofluorescence signal in a d good outcome (GO) and, e poor outcome (PO) patient sample. Scale bars = 100 µm; f Western blot analysis and g semi-quantitative analysis of Col1a1 expression in good and poor outcome patients. Signal intensity was used for quantitative analysis, and the intensity of the house-keeping gene (beta-actin) used for normalization; h association among eEF2 and Col1a1 expression, n = 18CC BY · PubMed Central
Fig. 4 eEF2 enhances healing processes in TNF-induced inflammatory fibroblast models. a–f eEF2 affects Col1a1 expression through autophagy in human fibroblasts. a, b Representative Western blot images and semi-quantitative analysis of LC3-II and LC3-II/LC3-I ratio, c–f representative Western blot (c) and confocal images (e) along with semi-quantitative analysis of Col1a1 (d, f) in cells treated with normal medium, starved medium for autophagy, si-eEF2 and 3-MA incubation based on autophagy, TNF was used afterward to create an inflammatory model; signal intensity (a–d) and fluorescent green intensity (e, f) were used for semi-quantitative analysis; g–i representative images captured by fluorescent microscope demonstrated the cell death and apoptosis when treated with normal condition, TNF and si-eEF2 and TNF: si-eEF2 increases the ratio of dead/live cells among primary fibroblast and fibroblast cell line; si-eEF2 positively associate with cell apoptosis among human fibroblasts h, j; the ratio of dead/live cells was reported by percentage and the apoptotic level of cells was presented by fluorescent green intensity. Data reported as mean ± SD, *p < 0.05, **p < 0.01, ***p < 0.001, scale bars = 100 µm, three replicates were used for quantitative analysis
Fig. 4 eEF2 enhances healing processes in TNF-induced inflammatory fibroblast models. a–f eEF2 affects Col1a1 expression through autophagy in human fibroblasts. a, b Representative Western blot images and semi-quantitative analysis of LC3-II and LC3-II/LC3-I ratio, c–f representative Western blot (c) and confocal images (e) along with semi-quantitative analysis of Col1a1 (d, f) in cells treated with normal medium, starved medium for autophagy, si-eEF2 and 3-MA incubation based on autophagy, TNF was used afterward to create an inflammatory model; signal intensity (a–d) and fluorescent green intensity (e, f) were used for semi-quantitative analysis; g–i representative images captured by fluorescent microscope demonstrated the cell death and apoptosis when treated with normal condition, TNF and si-eEF2 and TNF: si-eEF2 increases the ratio of dead/live cells among primary fibroblast and fibroblast cell line; si-eEF2 positively associate with cell apoptosis among human fibroblasts h, j; the ratio of dead/live cells was reported by percentage and the apoptotic level of cells was presented by fluorescent green intensity. Data reported as mean ± SD, *p < 0.05, **p < 0.01, ***p < 0.001, scale bars = 100 µm, three replicates were used for quantitative analysisCC BY · PubMed Central
Fig. 5 eEF2 enhances fibroblast proliferative processes. a, b Representative confocal images and semi-quantitative analysis of Col1a1 in primary fibroblasts and fibroblast cell line, with and without si-eEF2; c, d representative immunofluorescence images and number of proliferating human fibroblasts, with and without si-eEF2; e, f representative immunofluorescence images and ratio of dead/live fibroblasts, with and without si-eEF2; g, h representative immunofluorescence images and number of apoptotic cells from primary fibroblasts and fibroblast cell line, with and without si-eEF2; i–k representative images and quantitative analysis of cell migration rate assessed at 0 and 24 h in primary fibroblast and cell line, with and without si-eEF2. Data reported as mean ± SD, *p < 0.05, **p < 0.01, ***p < 0.001, scale bars = 100 µm, n = 3 replicates
Fig. 5 eEF2 enhances fibroblast proliferative processes. a, b Representative confocal images and semi-quantitative analysis of Col1a1 in primary fibroblasts and fibroblast cell line, with and without si-eEF2; c, d representative immunofluorescence images and number of proliferating human fibroblasts, with and without si-eEF2; e, f representative immunofluorescence images and ratio of dead/live fibroblasts, with and without si-eEF2; g, h representative immunofluorescence images and number of apoptotic cells from primary fibroblasts and fibroblast cell line, with and without si-eEF2; i–k representative images and quantitative analysis of cell migration rate assessed at 0 and 24 h in primary fibroblast and cell line, with and without si-eEF2. Data reported as mean ± SD, *p < 0.05, **p < 0.01, ***p < 0.001, scale bars = 100 µm, n = 3 replicatesCC BY · PubMed Central
Fig. 6 Potential mechanisms and eEF2 mode of action during inflammation and proliferation phases of dense connective tissue repair
Fig. 6 Potential mechanisms and eEF2 mode of action during inflammation and proliferation phases of dense connective tissue repairCC BY · PubMed Central

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Citations

Cites

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Metadata

Authors
Chen, J., Wang, J., Wu, X., Simon, N., Svensson, C. I., Yuan, J., Hart, D. A., Ahmed, A. S., & Ackermann, P. W.
Affiliations
  • Karolinska Institutet (SE)
  • Zhejiang Provincial People's Hospital (CN)
  • Peking University (CN)
  • University of Calgary (CA)
  • University of Helsinki (FI)
Corresponding author
  • Chen, Junyu
  • Ahmed, Aisha S
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2023-01-11
Volume
80
Issue
5
Pages
128-128
ISSN
1420-682X (ISSN-L)
DOI
10.21203/rs.3.rs-2424611/v1
PMC
PMC10121543
OpenAlex
W4366603743
Cited by
19
References
1
Citations by year
2026: 3 · 2025: 8 · 2024: 5 · 2023: 3
FWCI
5.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Life Sciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • European Commission (814244, HORIZON2020)
  • Karolinska Institutet
  • Knut och Alice Wallenbergs Stiftelse (2018.0161, 2019.0437)
  • Vetenskapsrådet (2017-00202, 2018-)
  • Centrum för idrottsforskning (2020-0019, 2022-0066)
  • Stiftelsen Konung Gustaf V:s 80-årsfond (FAI-2019-0611, FAI-2018-0524)
  • Reumatikerförbundet (R‐940565, R-968148)
  • Health and Medical Care Committee of the Regional Executive Board, Region Västra Götaland (SLL20180348)
  • H2020 Marie Skłodowska-Curie Actions (814244)
Topics
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Tendon Structure and Treatment
  • Health Sciences › Medicine › Surgery › Wound Healing and Treatments
  • Health Sciences › Dentistry › Periodontics › Periodontal Regeneration and Treatments
Keywords
elongation factor 2, Achilles tendon rupture, tissue repair, prognostic factors, proteomics, autophagy, apoptosis, cell proliferation, cell migration, patient-reported outcomes
MeSH terms
Achilles Tendon, Autophagy, Connective Tissue, Humans, Biomarkers, Cell Death, Apoptosis, Peptide Elongation Factor 2, Proteomics

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