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

Abstract

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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References

Aasen T , Raya A , Barrero MJ , et al. (2008) Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nature Biotechnology 26: 1276–1284.

Adli M (2018) The CRISPR tool kit for genome editing and beyond. Nature Communications 9: 1911.

Benam KH , Dauth S , Hassell B , et al. (2015) Engineered in vitro disease models. Annual Review of Pathology: Mechanisms of Disease 10: 195–262.

Briggs JA , Sun J , Shepherd J , et al. (2013) Integration‐free induced pluripotent stem cells model genetic and neural developmental features of down syndrome etiology. Stem Cells 31: 467–478.

Bursac N , Juhas M and Rando TA (2015) Synergizing engineering and biology to treat and model skeletal muscle injury and disease. Annual Review of Biomedical Engineering 17: 217–242.

Carroll D (2011) Genome engineering with zinc‐finger nucleases. Genetics 188: 773–782.

Cezar CA and Mooney DJ (2015) Biomaterial‐based delivery for skeletal muscle repair. Advanced Drug Delivery Reviews 84: 188–197.

Chal J and Pourquié O (2017) Making muscle: skeletal myogenesis in vivo and in vitro . Development 144: 2104–2122.

Darabi R , Santos FNC , Filareto A , et al. (2011) Assessment of the myogenic stem cell compartment following transplantation of Pax3/Pax7 ‐induced embryonic stem cell‐derived progenitors. Stem Cells 29: 777–790.

Darabi R , Arpke RW , Irion S , et al. (2012) Human ES‐ and iPS‐derived myogenic progenitors restore DYSTROPHIN and improve contractility upon transplantation in dystrophic mice. Cell Stem Cell 10: 610–619.

Davis RL , Weintraub H and Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51: 987–1000.

Engle SJ and Puppala D (2013) Integrating human pluripotent stem cells into drug development. Cell Stem Cell 12: 669–677.

Evans MJ and Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292: 154–156.

Freedman BS , Brooks CR , Lam AQ , et al. (2015) Modelling kidney disease with CRISPR‐mutant kidney organoids derived from human pluripotent epiblast spheroids. Nature Communications 6: 8715.

Fusaki N , Ban H , Nishiyama A , et al. (2009) Efficient induction of transgene‐free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proceedings of the Japan Academy, Series B 85: 348–362.

Han WM , Anderson SE , Mohiuddin M , et al. (2018) Synthetic matrix enhances transplanted satellite cell engraftment in dystrophic and aged skeletal muscle with comorbid trauma. Science Advances 4: eaar4008.

Hinson JT , Chopra A , Nafissi N , et al. (2015) Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science 349: 982–986.

Hochedlinger K , Yamada Y , Beard C , et al. (2005) Ectopic expression of Oct‐4 blocks progenitor‐cell differentiation and causes dysplasia in epithelial tissues. Cell 121: 465–477.

Hoshina A , Kawamoto T , Sueta S‐I , et al. (2018) Development of new method to enrich human iPSC‐derived renal progenitors using cell surface markers. Science Reports 8: 6375.

Itzhaki I , Maizels L , Huber I , et al. (2011) Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471: 225–229.

Joung JK and Sander JD (2013) TALENs: a widely applicable technology for targeted genome editing. Nature Reviews Molecular Cell Biology 14: 49–55.

Khetan S , Guvendiren M , Legant WR , et al. (2013) Degradation‐mediated cellular traction directs stem cell fate in covalently crosslinked three‐dimensional hydrogels. Nature Materials 12: 458–465.

Kiskinis E , Sandoe J , Williams LA , et al. (2014) Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell 14: 781–795.

Lancaster MA , Renner M , Martin C‐A , et al. (2013) Cerebral organoids model human brain development and microcephaly. Nature 501: 373–379.

Lee G , Papapetrou EP , Kim H , et al. (2009) Modelling pathogenesis and treatment of familial dysautonomia using patient‐specific iPSCs. Nature 461: 402–406.

Loh Y‐H , Agarwal S , Park I‐H , et al. (2009) Generation of induced pluripotent stem cells from human blood. Blood 113: 5476–5479.

Madden L , Juhas M , Kraus WE , et al. (2015) Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs. eLife 4: e04885.

Maeder ML and Gersbach CA (2016) Genome‐editing technologies for gene and cell therapy. Molecular Therapy 24: 430–446.

Maffioletti SM , Sarcar S , Henderson ABH , et al. (2018) Three‐dimensional human iPSC‐derived artificial skeletal muscles model muscular dystrophies and enable multilineage tissue engineering. Cell Reports 23: 899–908.

Mandal PK and Rossi DJ (2013) Reprogramming human fibroblasts to pluripotency using modified mRNA. Nature Protocols 8: 568–582.

Mendell JR , Kissel JT , Amato AA , et al. (1995) Myoblast transfer in the treatment of Duchenne's muscular dystrophy. New England Journal of Medicine 333: 832–838.

Okita K , Ichisaka T and Yamanaka S (2007) Generation of germline‐competent induced pluripotent stem cells. Nature 448: 313–317.

Okita K , Nakagawa M , Hyenjong H , et al. (2008) Generation of mouse induced pluripotent stem cells without viral vectors. Science 322: 949–953.

Pini V , Morgan JE , Muntoni F , et al. (2017) Genome editing and muscle stem cells as a therapeutic tool for muscular dystrophies. Current Stem Cell Reports 3: 137–148.

Quarta M , Brett JO , DiMarco R , et al. (2016) An artificial niche preserves the quiescence of muscle stem cells and enhances their therapeutic efficacy. Nature Biotechnology 34: 752–759.

Rao L , Qian Y , Khodabukus A , et al. (2018) Engineering human pluripotent stem cells into a functional skeletal muscle tissue. Nature Communications 9: 1–12.

Rashid ST , Corbineau S , Hannan N , et al. (2010) Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. Journal of Clinical Investigation 120: 3127–3136.

Sampaziotis F , Cardoso de Brito M , Madrigal P , et al. (2015) Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nature Biotechnology 33: 845–852.

Sánchez‐Danés A , Richaud‐Patin Y , Carballo‐Carbajal I , et al. (2012) Disease‐specific phenotypes in dopamine neurons from human iPS‐based models of genetic and sporadic Parkinson's disease. EMBO Molecular Medicine 4: 380–395.

Shoji E , Sakurai H , Nishino T , et al. (2015) Early pathogenesis of Duchenne muscular dystrophy modelled in patient‐derived human induced pluripotent stem cells. Science Reports 5: 1–13.

Smith AST , Davis J , Lee G , et al. (2016) Muscular dystrophy in a dish: engineered human skeletal muscle mimetics for disease modeling and drug discovery. Drug Discovery Today 21: 1387–1398.

Spence JR , Mayhew CN , Rankin SA , et al. (2011) Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470: 105–109.

Takahashi K and Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663–676.

Takahashi K , Tanabe K , Ohnuki M , et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861–872.

Tanaka A , Woltjen K , Miyake K , et al. (2013) Efficient and reproducible myogenic differentiation from human iPS cells: prospects for modeling Miyoshi Myopathy in vitro. PLoS One 8: e61540.

Thomson JA , Itskovitz‐Eldor J , Shapiro SS , et al. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282: 1145–1147.

Tulpule A , Kelley JM , Lensch MW , et al. (2013) Pluripotent stem cell models of Shwachman‐Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction. Cell Stem Cell 12: 727–736.

Uzel SGM , Platt RJ , Subramanian V , et al. (2016) Microfluidic device for the formation of optically excitable, three‐dimensional, compartmentalized motor units. Science Advances 2: e1501429–e1501429.

Yoshioka N , Gros E , Li H‐R , et al. (2013) Efficient generation of human iPSCs by a synthetic self‐replicative RNA. Cell Stem Cell 13: 246–254.

Yu J , Hu K , Smuga‐Otto K , et al. (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324: 797–801.

Zhou T , Benda C , Dunzinger S , et al. (2012) Generation of human induced pluripotent stem cells from urine samples. Nature Protocols 7: 2080–2089.

Further Reading

Cong L , Ran FA , Cox D , et al. (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339: 819–823.

Davies KE and Nowak KJ (2006) Molecular mechanisms of muscular dystrophies: old and new players. Nature Reviews Molecular Cell Biology 7: 762–773.

Gjorevski N , Sachs N , Manfrin A , et al. (2016) Designer matrices for intestinal stem cell and organoid culture. Nature 539: 560–564.

Israel MA , Yuan SH , Bardy C , et al. (2012) Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482: 216–220.

Jinek M , Chylinski K , Fonfara I , et al. (2012) A programmable dual‐RNA‐guided DNA endonuclease in adaptive bacterial immunity. Science 337: 816–821.

Juhas M , Engelmayr GC , Fontanella AN , et al. (2014) Biomimetic engineered muscle with capacity for vascular integration and functional maturation in vivo. Proceedings of the National Academy of Sciences 111: 5508–5513.

Liu C , Oikonomopoulos A , Sayed N , et al. (2018) Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development 145: dev156166.

Madl CM , Heilshorn SC and Blau HM (2018) Bioengineering strategies to accelerate stem cell therapeutics. Nature 557: 335–342.

Mali P , Yang L , Esvelt KM , et al. (2013) RNA‐guided human genome engineering via Cas9. Science 339: 823–826.

Tedesco FS and Cossu G (2012) Stem cell therapies for muscle disorders. Current Opinion in Neurology 25: 597–603.

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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. http://www.els.net [doi: 10.1002/9780470015902.a0028371]