Human Induced Pluripotent Stem Cells: Challenges and Opportunities in Developing New Therapies for Muscular Dystrophies


The generation of human induced pluripotent stem cells (iPSCs) has offered unparalleled opportunities for modelling human diseases and drug discovery. Muscular dystrophies are devastating inherited skeletal muscle disorders, for which there is no effective treatment. Recent breakthroughs in myogenic differentiation of iPSCs and other key technologies, including genome editing, smart biomaterials and tissue engineering, have opened new avenues to overcome the hurdles of developing therapies for previously incurable muscle diseases. The synergy between these novel technologies is increasingly transforming the fields of disease modelling, drug screening and regenerative medicine.

Key Concepts

  • Traditionally, muscular dystrophy research relies on primary human cells that have a limited expansion potential, and on animal models that do not fully recapitulate human pathophysiology.
  • The self‐renewal and differentiation properties of human induced pluripotent stem cells (iPSCs) make them an important resource for generating a large quantity of physiology‐relevant cell types to model human diseases in vitro.
  • In combination with genome editing and transgene‐free myogenic differentiation, human iPSCs can provide an unlimited supply of genetically corrected myogenic progenitor cells for autologous cell therapy and lay the basis for large‐scale drug screening.
  • Safety concerns regarding iPSCs and myogenic differentiation can be addressed by integration‐free reprogramming methods and transgene‐free differentiation protocols.
  • Recent breakthroughs in smart biomaterials and tissue engineering facilitate the transition from 2D monotypic to 3D multilineage cell cultures that resemble human tissue architecture.
  • The synergy between human iPSCs, genome editing, transgene‐free myogenic differentiation, advanced biomaterials and tissue engineering can exploit the full potential of human iPSCs and facilitate drug discovery and cell therapies, leading towards translation of biomedical research from bench to bedside.

Keywords: induced pluripotent stem cells; muscular dystrophy; genome editing; myogenic differentiation; disease models; cell therapy; drug screening; biomaterials; tissue engineering

Figure 1. An overview of patient‐specificiPSCsand potential applications. Patient‐specific iPSCs can be generated by reprogramming somatic cells, followed by genome editing to correct the mutation and generate isogenic control cells. By directed differentiation, the isogenic pairs of human iPSC‐derived cells can serve as a platform for disease modelling and drug discovery. In conjunction with tissue engineering technology, engineered 3D disease models can mimic human pathophysiology. In addition, the genetically corrected iPSCs can be differentiated to progenitor cells to be used in cell therapies. The engraftment efficacy may be further enhanced by biomaterial‐mediated delivery for iPSC‐derived progenitor cells.
Figure 2. Generation of isogenic pairs of humaniPSCsfor disease modelling. To control for inter‐individual variability due to different genetic backgrounds, isogenic pairs of human iPSCs should be used for disease modelling. In combination with genome editing technologies, isogenic pairs of control and disease iPSC models can be created by correcting mutations in mutant iPSCs or introducing mutations into normal iPSCs.
Figure 3. Genome editing technologies. Three genome editing systems, ZFN, TALEN and CRISPR have been developed to generate DNA double‐strand breaks (DSBs), which activate two DNA repair pathways: nonhomologous end joining (NHEJ) and homology‐dependent repair (HDR). The NHEJ pathway does not require a template, whereas the HDR pathway uses a homologous DNA donor template for homologous recombination. By modifying the donor template, targeted gene modification can be achieved.


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Paredes‐Redondo, Amaia, and Lin, Yung‐Yao(Mar 2019) Human Induced Pluripotent Stem Cells: Challenges and Opportunities in Developing New Therapies for Muscular Dystrophies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028371]