Induced pluripotent stem cell platforms for disease modelling of skeletal muscle laminopathies

• Main Author: Steele-Stallard, Heather
• Published: University College London (University of London) 2018
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.763210

Laminopathies are a clinically and genetically heterogeneous group of 16 disorders caused by mutations in LMNA. This gene codes for lamin A and lamin C, which together with lamin B1 and B2 form the nuclear lamina, a mesh-like structure located underneath the inner nuclear membrane. Laminopathy disorders show striking tissue specificity, with subtypes affecting striated muscle, peripheral nerve, and others causing multisystem disease with accelerated aging. The exact mechanisms underlying the pathology of laminopathies, and the cause of the tissue specific phenotypes are unknown, although several mechanisms have been proposed. Understanding the pathology of these disorders is limited by the rarity of cases, and lack of easily accessible cell types. Induced pluripotent stem cells (iPSCs) can be derived from easily accessible cell types, have unlimited proliferation potential, and can be differentiated into cell types that would otherwise be difficult and invasive to obtain. This PhD project aimed to use iPSCs from patients with skeletal muscle laminopathies to model disease phenotypes in vitro. In this thesis, fibroblasts from a patient with a skeletal muscle laminopathy were reprogrammed into iPSCs. This line, along with three already reprogrammed iPSC lines from skeletal muscle laminopathy patients were differentiated into mesodermal/mesenchymal progenitors, myogenic precursor cells and myotubes. Disease-associated phenotypes were observed in these cells, namely abnormal nuclear shape and mislocalisation of nuclear lamina proteins. Furthermore, work towards developing a therapy based on lamin A/C exon skipping was conducted. These results demonstrate that iPSCs from skeletal muscle laminopathy patients can be used to model disease-associated phenotypes in vitro. This lays the foundation for future therapy testing and disease modelling in skeletal muscle laminopathies using patient specific iPSCs.