Jiang, Yunsong; (2025) Developing Advanced Human Myo-ECM 3D Models for Disease Modelling and Therapy Development. Doctoral thesis (Ph.D), UCL (University College London).

Text Jiang_thesis.pdf - Submitted Version Access restricted to UCL open access staff until 1 July 2026. Download (61MB)

Abstract

The skeletal muscle's extracellular matrix (ECM) is a three-dimensional (3D), noncellular scaffold predominantly produced by muscle-resident fibroblasts (also known as fibro-adipogenic progenitors, FAPs). It plays essential roles in structural stability, force transmission, and regulation of muscle development, homeostasis, and regeneration. Pathogenic variants in genes encoding key ECM components, such as collagen type VI (COLVI), result in a group of muscle disorders termed COLVI-related dystrophies (COLVI-RDs). Despite the existence of mouse models and primary patient-derived cell cultures, these disorders, including severe cases like Ullrich congenital muscular dystrophy (UCMD), are poorly understood and lack effective treatments. Therefore, the development of humanised models that emulate critical disease characteristics in vitro is critical for understanding disease mechanisms and for advancing precision diagnosis and therapy. In this study, an advanced human myo-ECM 3D model that recreates muscle-matrix interaction mimicking the native human skeletal muscle tissues was developed. This model encapsulated both COLVI matrix from fibroblasts and aligned, striated myotubes from skeletal myogenic cells. This myo-ECM 3D model also serves as a reliable disease model for UCMD, reflecting key physiological and functional disease hallmarks such as macroscopic phenotype akin to joint contractures seen in COLVIRD patients, reduced muscle contractility and abnormal increase in tissue stiffness. To assist future establishment of an isogenic myo-ECM model, a novel human induced pluripotent stem cell (iPSC) line derived from UCMD patient and its isogonic iPSC line generated using CRISPR-based gene editing tool were derived and characterised. Thus, the developed myo-ECM 3D platform offers a promising tool for uncovering novel insights into COLVI-RD pathomechanisms, establishing genotype-phenotype correlations, and identifying early pathogenic features in vitro. This platform paves the way for further etiological and prognostic studies and supports the development of future therapies for COLVI-RDs.

Download activity - last month

Export as XMLCSVJSON

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as XMLCSVJSON

Archive Staff Only

View Item