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Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255705 | GEO | 2024/02/19

REPOSITORIES: GEO

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Project description:Mutations in Lissencephaly 1 (LIS1) result in various human brain developmental diseases, such as changes in brain structure, lissencephaly, and epilepsy. RNA-sequencing data from on-chip organoids derived from human embryonic stem cells (hESCs) revealed significant changes in the expression of extracellular matrix (ECM) – related genes in LIS1+/- samples. This project examined the biomechanical properties of LIS1+/- mutated and healthy hESCs-derived cortical organoids. A rheological test using the pipette aspiration technique revealed that LIS1+/- cortical organoids are stiffer than control organoids. The increased stiffness of the LIS1+/- cortices was proportional to an increased expression of the nuclear mechano-sensing protein, Lamin A, highlighting the adverse cellular and nuclear changes underlying the stiffening of LIS1+/- organoids. To delineate the ECM composition associated with the stiffening effect in LIS1+/-, healthy and mutated hippocampal and cortical organoids were examined at the protein, mRNA, and miRNA levels. Whole RNA sequencing showed altered expression of multiple collagen-related pathways, including the 'collagens containing ECM' and the 'Collagen trimer' pathways. Differential mRNA expression has inversely correlated with the expression of their targeting miRNAs in the LIS1+/- organoids. This inverse miRNA-mRNA expression was most pronounced in genes associated with the ECM-receptor signalling pathway. At the protein level, the mutated hippocampal organoids showed unilateral, substantial increased expression of collagens and proteins involved in collagen synthesis, modification, and remodelling. Following a collagenolytic treatment with the catalytic domain of the MMP9 enzyme, the stiffness levels in the LIS1+/- organoids were reduced to control values. Overall, this work provides new information about the role of LIS1 in controlling collagen expression and the abnormal mechanical properties associated with mutation to the LIS1 gene in the development of the human cortex and hippocampus.

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Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2

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