Unravelling the Impact of Cyclic Mechanical Stretch in Keratoconus—A Transcriptomic Profiling Study
Abstract
:1. Introduction
2. Results
2.1. Identification of Differentially Expressed Genes
2.2. Droplet Digital PCR (ddPCR) Validation of Differentially Expressed Genes
3. Discussion
3.1. Overview
3.2. Differentially Expressed Genes in HKCs vs. HCFs and KC-Altered Genes Responsive to TGFβ1 Treatment
3.3. KC-Altered Genes Responsive to CMS
3.4. Limitations of Our Study
3.5. Conclusions
4. Materials and Methods
4.1. Culture of Primary Human Corneal Fibroblasts (HCFs) and KC-Derived Cells (HKCs)
4.2. RNA Extraction, Quality Check, Sequencing and Analysis
4.3. Validation of Differentially Expressed Genes Using ddPCR
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene Symbol | Gene Description | Fold Change | FDR-Adjusted p-Value |
---|---|---|---|
Upregulated DEGs | |||
MTCO1P12 | Mitochondrially Encoded Cytochrome C Oxidase I Pseudogene 12 | 39.9 | 1.87 × 10−2 |
GSTT2B | Glutathione S-Transferase Theta-2B | 8.1 | 9.78 × 10−24 |
PCDHB3 | Protocadherin Beta-3 | 6.5 | 8.83 × 10−8 |
SIK1 | Salt Inducible Kinase 1 | 4.4 | 1.63 × 10−4 |
SMG1P4 | SMG1 Pseudogene 4 | 4.1 | 2.62 × 10−3 |
CDH10 | Cadherin 10 | 3.5 | 4.75 × 10−3 |
RP11-649E7.5 | No description yet | 3.1 | 9.74 × 10−3 |
LAMC2 | Laminin Subunit Gamma 2 | 3.0 | 4.87 × 10−3 |
NOTCH2NLB | Notch 2 N-Terminal Like B | 2.8 | 7.57 × 10−2 |
PDPN | Podoplanin | 2.8 | 7.59 × 10−5 |
Downregulated DEGs | |||
FBN2 | Fibrillin 2 | −200.9 | 3.09 × 10−4 |
SLC8A1 | Solute Carrier Family 8 Member A1 | −25.4 | 3.83 × 10−3 |
SORT1 | Sortilin 1 | −17.2 | 9.82 × 10−3 |
PKD1P2 | Polycystin 1, Transient Receptor Potential Channel Interacting Pseudogene 2 | −17.2 | 2.03 × 10−2 |
ITGA7 | Integrin Subunit Alpha 7 | −11.8 | 1.96 × 10−3 |
AQP1 | Aquaporin 1 (Colton blood group) | −9.6 | 4.69 × 10−3 |
DUSP4 | Dual Specificity Phosphatase 1 | −9.0 | 3.08 × 10−5 |
ELN | Elastin | −8.6 | 2.69 × 10−2 |
OXTR | Oxytocin Receptor | −8.0 | 1.85 × 10−5 |
EPHB6 | EPH Receptor B6 | −7.8 | 2.37 × 10−4 |
Gene Symbol | Gene Description | HKCs (TGFβ1 + CMS) vs. HCFs (TGFβ1 + CMS) | HCF (+/− 10 ng/mL TGFβ1 and CMS) | ||
---|---|---|---|---|---|
Fold Change | FDR-Adjusted p-Value | Fold Change | FDR-Adjusted p-Value | ||
Upregulated DEGs | |||||
LIPG | Lipase G, Endothelial Type | 2.1 | 1.46 × 10−2 | 9.4 | 4.27 × 10−5 |
LAMC2 | Laminin Subunit Gamma 2 | 3.0 | 4.87 × 10−3 | 4.5 | 2.55 × 10−6 |
MYO1D | Myosin 1D | 1.7 | 1.87 × 10−2 | 3.4 | 1.72 × 10−2 |
BHLHE40 | Basic Helix-Loop-Helix Family Member E40 | 1.7 | 1.55 × 10−3 | 3.1 | 2.67 × 10−9 |
SYT15 | Synaptotagmin 15 | 1.7 | 2.27 × 10−2 | 2.7 | 5.11 × 10−2 |
CSMD2 | CUB And Sushi Multiple Domains 2 | 1.6 | 1.64 × 10−2 | 2.5 | 3.41 × 10−2 |
Downregulated DEGs | |||||
NPTX1 | Neuronal pentraxin 1 | −2.0 | 1.01 × 10−2 | −10.1 | 1.44 × 10−14 |
CEMIP | Cell migration inducing hyaluronidase 1 | −2.3 | 4.52 × 10−2 | −8.7 | 2.27 × 10−26 |
IFI35 | Interferon induced protein 35 | −1.7 | 3.01 × 10−2 | −8.0 | 5.52 × 10−5 |
SECTM1 | Secreted And Transmembrane 1 | −3.7 | 1.59 × 10−3 | −7.9 | 1.10 × 10−4 |
CLDN11 | Claudin 11 | −1.6 | 4.78 × 10−3 | −5.3 | 8.50 × 10−19 |
KCNJ2 | Potassium inwardly rectifying channel subfamily J member 2 | −1.6 | 5.40 × 10−2 | −4.8 | 1.65 × 10−6 |
ALDH3A1 | Aldehyde Dehydrogenase 3 Family Member A1 | −3.9 | 2.47 × 10−2 | −4.7 | 5.49 × 10−5 |
PLPP3 | Phospholipid Phosphatase 3 | −1.6 | 4.01 × 10−2 | −4.6 | 4.44 × 10−17 |
GREM2 | Gremlin 2, DAN family BMP antagonist | −2.0 | 4.97 × 10−3 | −4.5 | 2.42 × 10−11 |
GJD3 | Gap Junction Protein Delta 3 | −2.1 | 2.54 × 10−2 | −4.3 | 5.06 × 10−2 |
Gene Symbol | Gene Description/Homology | Fold Change | FDR-Adjusted p-Value (HKC vs. HCF) | Correlation (Conc (ng/mL)) | FDR-Adjusted p-Value (Conc (ng/mL)) |
---|---|---|---|---|---|
Positive correlation | |||||
SEMA7A | Semaphorin 7A (John Milton Hagen Blood Group) | −1.6 | 3.74 × 10−2 | 0.7 | 1.19 × 10−5 |
TENM4 | Teneurin Transmembrane Protein 4 | −1.6 | 1.14 × 10−2 | 0.7 | 1.95 × 10−5 |
PSD4 | Pleckstrin and Sec7 Domain Containing 4 | −2.4 | 5.46 × 10−7 | 0.7 | 3.97 × 10−5 |
POU2F2 | POU Class 2 Homeobox 2 | −1.9 | 2.71 × 10−6 | 0.6 | 9.02 × 10−5 |
COL7A1 | Collagen Type VII Alpha 1 Chain | −2.0 | 1.59 × 10−3 | 0.6 | 9.31 × 10−5 |
ZNF365 | Zinc Finger Protein 365 | −3.2 | 1.02 × 10−3 | 0.6 | 9.88 × 10−5 |
CNN1 | Calponin 1 | −2.5 | 1.93 × 10−3 | 0.6 | 9.88 × 10−5 |
UCN2 | Urocortin 2 | −2.0 | 3.58 × 10−3 | 0.6 | 1.11 × 10−4 |
PFKFB4 | 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 | −1.9 | 1.91 × 10−3 | 0.6 | 1.59 × 10−4 |
BTBD11 | Homo sapiens KBTBD11 antisense RNA 1 (KBTBD11-AS1) | −1.8 | 6.40 × 10−4 | 0.6 | 2.22 × 10−4 |
Negative correlation | |||||
SSH3 | Slingshot Protein Phosphatase 3 | −1.5 | 2.92 × 10−4 | −0.8 | 1.35 × 10−6 |
IFI35 | Interferon Induced Protein 35 | −1.7 | 3.01 × 10−2 | −0.7 | 2.63 × 10−6 |
CLDN11 | Claudin 11 | −1.6 | 4.78 × 10−3 | −0.7 | 2.83 × 10−6 |
BCAM | Basal Cell Adhesion Molecule (Lutheran Blood Group) | −2.1 | 8.10 × 10−6 | −0.7 | 1.26 × 10−5 |
CCN3 | Cellular Communication Network Factor 3 | 1.7 | 1.06 × 10−2 | −0.7 | 1.64 × 10−5 |
CD248 | CD248 Molecule | −1.5 | 1.47 × 10−3 | −0.7 | 1.72 × 10−5 |
PLPP3 | Phospholipid Phosphatase 3 | −1.6 | 4.01 × 10−2 | −0.7 | 2.25 × 10−5 |
SECTM1 | Secreted and Transmembrane 1 | −3.7 | 1.59 × 10−3 | −0.7 | 2.76 × 10−5 |
AHRR | Aryl Hydrocarbon Receptor Repressor | −1.9 | 3.99 × 10−4 | −0.7 | 5.36 × 10−5 |
GREM2 | Gremlin 2, DAN Family BMP Antagonist | −2.0 | 4.97 × 10−3 | −0.7 | 5.74 × 10−5 |
Gene Symbol | Gene Description or Homology | Fold Change | FDR-Adjusted p-Value (HKC vs. HCF) | FDR-Adjusted p-Value (Stretch) |
---|---|---|---|---|
DDAH2 | Dimethylarginine Dimethylaminohydrolase 2 | −1.7 | 3.17 × 10−8 | 1.96 × 10−2 |
OBSCN | Obscurin, Cytoskeletal Calmodulin And Titin-Interacting RhoGEF | −2.7 | 2.37 × 10−7 | 7.36 × 10−2 |
CLU | Clusterin | −1.9 | 1.49 × 10−5 | 4.53 × 10−2 |
LINC00565 | Homo sapiens chromosome 13 open reading frame 46 (C13orf46) | −1.6 | 1.86 × 10−5 | 2.30 × 10−2 |
RP11-1334A24.5 | No description yet | −1.9 | 3.20 × 10−5 | 1.92 × 10−2 |
HDAC5 | Histone Deacetylase 5 | −1.5 | 6.45 × 10−5 | 9.94 × 10−3 |
AK4 | Adenylate Kinase 4 | 1.7 | 5.78 × 10−4 | 1.12 × 10−2 |
GSN-AS1 | GSN Antisense RNA 1 | −1.7 | 9.95 × 10−4 | 9.65 × 10−2 |
RPLP0P2 | Ribosomal Protein Lateral Stalk Subunit P0 Pseudogene 2 | −2.1 | 1.36 × 10−3 | 7.98 × 10−2 |
ITGA10 | Integrin Subunit Alpha 10 | −2.1 | 2.12 × 10−3 | 1.84 × 10−3 |
KCNS3 | Potassium Voltage-Gated Channel Modifier Subfamily S Member 3 | −1.5 | 2.33 × 10−3 | 5.18 × 10−2 |
CLDN11 | Claudin 11 | −1.6 | 4.78 × 10−3 | 4.04 × 10−2 |
F2RL1 | F2R Like Trypsin Receptor 1 | −2.2 | 7.18 × 10−3 | 6.15 × 10−2 |
Gene Symbol | Gene Description/Homology | Fold Change | FDR-Adjusted p-Value (HKC vs. HCF) | Correlation (Conc (ng/mL)) | FDR-Adjusted p-Value (Conc (ng/mL)) | FDR-Adjusted p-Value (Stretch) |
---|---|---|---|---|---|---|
DDAH2 | Dimethylarginine Dimethylaminohydrolase 2 | −1.7 | 3.17 × 10−8 | −0.4 | 3.49 × 10−2 | 1.96 × 10−2 |
CLU | Clusterin | −1.9 | 1.49 × 10−5 | −0.2 | 3.75 × 10−3 | 4.53 × 10−2 |
LINC00565 | Homo sapiens chromosome 13 open reading frame 46 (C13orf46) | −1.6 | 1.86 × 10−5 | 0.5 | 5.64 × 10−4 | 2.30 × 10−2 |
RP11-1334A24.5 | No description yet | −1.9 | 3.20 × 10−5 | 0.6 | 1.02 × 10−3 | 1.92 × 10−2 |
CLDN11 | Claudin 11 | −1.6 | 4.78 × 10−3 | 0.6 | 2.83 × 10−6 | 4.04 × 10−2 |
F2RL1 | F2R Like Trypsin Receptor 1 | −2.2 | 7.18 × 10−3 | −0.1 | 1.00 × 10−2 | 6.15 × 10−2 |
Gene Symbol | Gene Name | ddPCR | RNA-Seq | ||
---|---|---|---|---|---|
Effect Size (HKCs vs. HCFs) | p-Value (HKCs vs. HCFs) | Fold Change (HKCs vs. HCFs) | FDR-Adjusted p-Value (HKCs vs. HCFs) | ||
COL7A1 | Collagen type VII alpha 1 chain | 11.7 | 6.39 × 10−4 | −2.0 | 1.59 × 10−3 |
SCARA3 | Scavenger receptor class A member 3 | 18.3 | 7.57 × 10−6 | −2.0 | 2.62 × 10−3 |
SERPINF1 | Serpin family F member 1 | −23.4 | 4.90 × 10−4 | −2.4 | 3.19 × 10−4 |
FBN2 | Fibrillin 2 | −4.2 | 1.28 × 10−1 | −200.9 | 3.09 × 10−4 |
Gene Symbol | Gene Name | ddPCR | RNA-Seq | ||||||
---|---|---|---|---|---|---|---|---|---|
Effect Size (HKCs vs. HCFs) | p-Value (HKCs vs. HCFs) | Effect Size (TGFβ1 Treatment) | p-Value (TGFβ1 Treatment) | Fold Change (HKCs vs. HCFs) | FDR- Adjusted p-Value (HKCs vs. HCFs) | Correlation (Conc (ng/mL)) | FDR- Adjusted p-Value (TGFβ1 Treatment) | ||
COL7A1 | Collagen type VII alpha 1 chain | 11.7 | 6.39 × 10−4 | 1.8 | 3.75 × 10−5 | −2.0 | 1.59 × 10−3 | 0.6 | 9.31 × 10−5 |
SERPINF1 | Serpin family F member 1 | −23.4 | 4.90 × 10−4 | −2.3 | 7.21 × 10−3 | −2.0 | 3.19 × 10−4 | −0.4 | 1.64 × 10−2 |
Gene Symbol | Gene Name | ddPCR | RNA-Seq | ||||
---|---|---|---|---|---|---|---|
Effect Size (HKCs vs. HCFs) | p-Value (HKCs vs. HCFs) | p-Value (Stretch) | Fold Change (HKCs vs. HCFs) | FDR-Adjusted p-Value (HKCs vs. HCFs) | FDR-Adjusted p-Value (Stretch) | ||
CLU | Clusterin | −5.4 | 0.1695 | 0.0952 | −1.9 | 1.49 × 10−5 | 4.53 × 10−2 |
Gene Symbol | Gene Name | ddPCR | RNA-Seq | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Fold Change (HKCs vs. HCFs) | p-Value (HKCs vs. HCFs) | Effect Size (TGFβ1 Treatment) | p-Value (TGFβ1 Treatment) | p-Value (Stretch) | Fold Change (HKCs vs. HCFs) | FDR-Adjusted p-Value (HKCs vs. HCFs) | Correlation (Conc (ng/mL)) | FDR- Adjusted p-Value (TGFβ1 Treatment) | FDR- Adjusted p-Value (Stretch) | ||
CLU | Clusterin | −5.4 | 0.1695 | 0.8 | 0.0979 | 0.0952 | −1.9 | 1.49 × 10−5 | −0.2 | 3.75 × 10−3 | 4.53 × 10−2 |
Sample ID | Age (y/o) | Gender | Ethnicity | Cause of Death |
---|---|---|---|---|
HCF-1 | 65 | Male | Caucasian | Cardiopulmonary Arrest (CPA) |
HCF-2 | 63 | Male | Caucasian | Acute STEMI |
HCF-3 | 72 | Female | Caucasian | Motor vehicle accident (MVA) |
HCF-4 | 71 | Male | Caucasian | Cardiorespiratory Failure |
HKC-1 | 43 | Female | Unknown | N/A (transplant patient) |
HKC-2 | 19 | Male | Unknown | N/A (transplant patient) |
HKC-3 | 69 | Male | Unknown | N/A (transplant patient) |
HKC-4 | 31 | Male | African American | N/A (transplant patient) |
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Akoto, T.; Cai, J.; Nicholas, S.; McCord, H.; Estes, A.J.; Xu, H.; Karamichos, D.; Liu, Y. Unravelling the Impact of Cyclic Mechanical Stretch in Keratoconus—A Transcriptomic Profiling Study. Int. J. Mol. Sci. 2023, 24, 7437. https://doi.org/10.3390/ijms24087437
Akoto T, Cai J, Nicholas S, McCord H, Estes AJ, Xu H, Karamichos D, Liu Y. Unravelling the Impact of Cyclic Mechanical Stretch in Keratoconus—A Transcriptomic Profiling Study. International Journal of Molecular Sciences. 2023; 24(8):7437. https://doi.org/10.3390/ijms24087437
Chicago/Turabian StyleAkoto, Theresa, Jingwen Cai, Sarah Nicholas, Hayden McCord, Amy J. Estes, Hongyan Xu, Dimitrios Karamichos, and Yutao Liu. 2023. "Unravelling the Impact of Cyclic Mechanical Stretch in Keratoconus—A Transcriptomic Profiling Study" International Journal of Molecular Sciences 24, no. 8: 7437. https://doi.org/10.3390/ijms24087437