Cheesbrough, Aimee;
Harley, Peter;
Riccio, Federica;
Wu, Lei;
Song, Wenhui;
Lieberam, Ivo;
(2023)
A scalable human iPSC-based neuromuscular disease model on suspended biobased elastomer nanofiber scaffolds.
Biofabrication
, 15
(4)
, Article 045020. 10.1088/1758-5090/acf39e.
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Abstract
Many devastating neuromuscular diseases currently lack effective treatments. This is in part due to a lack of drug discovery platforms capable of assessing complex human neuromuscular disease phenotypes in a scalable manner. A major obstacle has been generating scaffolds to stabilise mature contractile myofibers in a multi-well assay format amenable to high content image analysis (HCI). This study describes the development of a scalable human iPSC-neuromuscular disease model, whereby suspended elastomer nanofibers support long-term stability, alignment, maturation, and repeated contractions of iPSC-myofibers, innervated by iPSC-motor neurons in 96-well assay plates. In this platform, optogenetic stimulation of the motor neurons elicits robust myofiber-contractions, providing a functional readout of neuromuscular transmission. Additionally, HCI provides rapid and automated quantification of axonal outgrowth, myofiber morphology, and neuromuscular synapse number and morphology. By incorporating amyotrophic lateral sclerosis (ALS)-related TDP-43G298S mutant motor neurons and CRISPR-corrected controls, key neuromuscular disease phenotypes are recapitulated, including weaker myofiber contractions, reduced axonal outgrowth, and reduced number of neuromuscular synapses. Treatment with a candidate ALS drug, the receptor-interacting protein kinase-1 (RIPK1)-inhibitor necrostatin-1, rescues these phenotypes in a dose-dependent manner, highlighting the potential of this platform to screen novel treatments for neuromuscular diseases.
| Type: | Article |
|---|---|
| Title: | A scalable human iPSC-based neuromuscular disease model on suspended biobased elastomer nanofiber scaffolds |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1088/1758-5090/acf39e |
| Publisher version: | http://dx.doi.org/10.1088/1758-5090/acf39e |
| Language: | English |
| Additional information: | Original content from this work may be used under the terms of the Creative Commons Attribution 4.0 license. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI. |
| Keywords: | CRISPR-Cas9, amyotrophic lateral sclerosis, biobased elastomer nanofibers, high content image analysis, human induced pluripotent stem cells, optogenetics, scalable neuromuscular disease modelling |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10176482 |
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