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| Status |
Public on Feb 19, 2024 |
| Title |
Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Matrix stiffening by lysyl oxidase-like 2 (LOXL2) mediated collagen cross-linking is proposed as a core feed-forward mechanism that promotes fibrogenesis. Failure in clinical trials of simtuzumab (the humanized version of AB0023, a monoclonal antibody against human LOXL2) suggested targeting LOXL2 may not have disease relevance, however target engagement was not directly evaluated. We compared the spatial transcriptome of active human lung fibrogenesis sites with different human cell culture models to determine the model with greatest disease relevance. Within the selected model system, we then evaluated AB0023, identifying that it did not inhibit collagen cross-linking or reduce tissue stiffness, nor did it inhibit LOXL2 catalytic activity. In contrast it did potently inhibit angiogenesis consistent with an alternative, non-enzymatic mechanism of action. Thus, AB0023 is anti-angiogenic but does not inhibit LOXL2 catalytic activity, collagen cross-linking or tissue stiffening. These findings have implications for the interpretation of lack of efficacy of simtuzumab in clinical trials of fibrotic diseases.
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| Overall design |
To compare different model systems for fiboblastic foci, we cultured primary fibroblasts in different culture conditions including standard 2D culture, 2D culture with ficoll (scar-in-a-jar), and 3D spheroids, with and without the profibrotic cytokine TGF-β
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| Contributor(s) |
Bell JA, Davies ER, Brereton CJ, Vukmirovic M, Roberts JJ, Lunn K, Wickens L, Conforti F, Ridley RA, Alzetani A, Jogai S, Marshall BG, Fabre A, Richeldi L, Monk PD, Skipp P, Kaminski N, Offer E, Wang Y, Davies DE, Jones MG |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Feb 13, 2024 |
| Last update date |
Feb 19, 2024 |
| Contact name |
Joseph Bell |
| E-mail(s) |
J.A.Bell@soton.ac.uk
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| Organization name |
Clinical and Experimental Sciences, Southampton General Hospital
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| Department |
Medicine
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| Lab |
Brooke Laboratory
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| Street address |
Tremona Road
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| City |
SOUTHAMPTON |
| State/province |
Hampshire |
| ZIP/Postal code |
SO16 6YD |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (48)
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| GSM8078215 |
Fibroblasts, 48hr 2D No TGFB, rep4 |
| GSM8078216 |
Fibroblasts, 48hr 2D +TGFB, rep1 |
| GSM8078217 |
Fibroblasts, 48hr 2D +TGFB, rep2 |
| GSM8078218 |
Fibroblasts, 48hr 2D +TGFB, rep3 |
| GSM8078219 |
Fibroblasts, 48hr 2D +TGFB, rep4 |
| GSM8078220 |
Fibroblasts, 2 week 2D No TGFB, rep1 |
| GSM8078221 |
Fibroblasts, 2 week 2D No TGFB, rep2 |
| GSM8078222 |
Fibroblasts, 2 week 2D No TGFB, rep3 |
| GSM8078223 |
Fibroblasts, 2 week 2D No TGFB, rep4 |
| GSM8078224 |
Fibroblasts, 2 week 2D +TGFB, rep1 |
| GSM8078225 |
Fibroblasts, 2 week 2D +TGFB, rep2 |
| GSM8078226 |
Fibroblasts, 2 week 2D +TGFB, rep3 |
| GSM8078227 |
Fibroblasts, 2 week 2D +TGFB, rep4 |
| GSM8078228 |
Fibroblasts, 72hr Ficoll No TGFB, rep1 |
| GSM8078229 |
Fibroblasts, 72hr Ficoll No TGFB, rep2 |
| GSM8078230 |
Fibroblasts, 72hr Ficoll No TGFB, rep3 |
| GSM8078231 |
Fibroblasts, 72hr Ficoll No TGFB, rep4 |
| GSM8078232 |
Fibroblasts, 72hr Ficoll +TGFB, rep1 |
| GSM8078233 |
Fibroblasts, 72hr Ficoll +TGFB, rep2 |
| GSM8078234 |
Fibroblasts, 72hr Ficoll +TGFB, rep3 |
| GSM8078235 |
Fibroblasts, 72hr Ficoll +TGFB, rep4 |
| GSM8078236 |
Fibroblasts, 2 week Ficoll No TGFB, rep1 |
| GSM8078237 |
Fibroblasts, 2 week Ficoll No TGFB, rep2 |
| GSM8078238 |
Fibroblasts, 2 week Ficoll No TGFB, rep3 |
| GSM8078239 |
Fibroblasts, 2 week Ficoll No TGFB, rep4 |
| GSM8078240 |
Fibroblasts, 2 week Ficoll +TGFB, rep1 |
| GSM8078241 |
Fibroblasts, 2 week Ficoll +TGFB, rep2 |
| GSM8078242 |
Fibroblasts, 2 week Ficoll +TGFB, rep3 |
| GSM8078243 |
Fibroblasts, 2 week Ficoll +TGFB, rep4 |
| GSM8078244 |
Fibroblasts, 2 week 3D No TGFB, rep1 |
| GSM8078245 |
Fibroblasts, 2 week 3D No TGFB, rep2 |
| GSM8078246 |
Fibroblasts, 2 week 3D No TGFB, rep3 |
| GSM8078247 |
Fibroblasts, 2 week 3D No TGFB, rep4 |
| GSM8078248 |
Fibroblasts, 2 week 3D +TGFB, rep1 |
| GSM8078249 |
Fibroblasts, 2 week 3D +TGFB, rep2 |
| GSM8078250 |
Fibroblasts, 2 week 3D +TGFB, rep3 |
| GSM8078251 |
Fibroblasts, 2 week 3D +TGFB, rep4 |
| GSM8078252 |
Fibroblasts, 6 week 3D No TGFB, rep1 |
| GSM8078253 |
Fibroblasts, 6 week 3D No TGFB, rep2 |
| GSM8078254 |
Fibroblasts, 6 week 3D No TGFB, rep3 |
| GSM8078255 |
Fibroblasts, 6 week 3D No TGFB, rep4 |
| GSM8078256 |
Fibroblasts, 6 week 3D +TGFB, rep1 |
| GSM8078257 |
Fibroblasts, 6 week 3D +TGFB, rep2 |
| GSM8078258 |
Fibroblasts, 6 week 3D +TGFB, rep3 |
| GSM8078259 |
Fibroblasts, 6 week 3D +TGFB, rep4 |
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| Relations |
| BioProject |
PRJNA1076201 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE255705_raw_counts.txt.gz |
2.5 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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