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Step Forward in Modelling Aggregation Based Disease

“Modeling Human Protein Aggregation Cardiomyopathy Using Murine Induced Pluripotent Stem Cells”

From Stem Cells Translational Medicine

Mutations in the heat shock protein αB-crystallin (CryAB) are linked to skeletal and cardiac myopathies (Rajasekaran et al, Vicart et al and Wang et al) with one specific mutation (R120G) also leading to the formation of large cytoplasmic aggregates (Bova et al and Maloyan et al). To model this mutation, researchers from the laboratory of Ivor Benjamin at the Departments of Internal Medicine and Biochemistry, Salt Lake City, Utah, USA have taken advantage of an existing transgenic R120G mouse model to generate induced pluripotent stem cells (iPSCs) and differentiate them into cardiomyocytes. From here they show that these disease specific iPSCs recapitulate both key hallmarks of this mutation found in animal models and patients, CryAB protein aggregation and cellular hypertrophy, thereby presenting an attractive cell model system for further research (Limphong and Zhang et al).

iPSCs were retrovirally generated from one transgenic (TG) male harbouring the R120G CryAB  mutation and one non-TG (NTG) male, and could be differentiated efficiently into beating embryoid bodies (EBs). TG EBs exhibited markedly increased levels of CryAB mRNA and protein, with protein being found in both detergent-soluble and insoluble fractions, as compared to NTG EBs. Cardiomyocytes (CMs) within the EBs were identified through cardiac-specific marker troponin T (cTnT) protein expression, with 57% of CMs containing CryAB protein aggregates. Additionally TG-CMs with high levels of CryAB expression were significantly larger in size relative to low CryAB expressing TG-CMs and NTG-CMs. Finally, increased expression of foetal genes, indicative of cardiac hypertrophy, was also observed in TG-CMs, which together with subsequent data suggests that CMs derived from disease specific iPSCs can be efficiently be used to model this specific CryAB protein-related disease.

While CM production from iPSCs has allowed for the modelling of many related diseases (Moretti et al, Sun et al and Yazawa et al), this study is the first to report the recapitulation of the specific disease pathologies related to the R120G mutant. The authors note that “Ongoing projects in our laboratory are establishing a patient-specific iPSC model containing CryAB mutations”, which will hopefully lead to the delineation of disease progression and provide a screening tool for future therapeutics.

 

References

  • Bova MP et al. Mutation R120G in alphaB-crystallin, which is linked to a desmin-related myopathy, results in an irregular structure and defective chaperone-like function. Proc Natl Acad Sci USA 1999;96: 6137–6142.
  • Maloyan A et al. Exercise reverses preamyloid oligomer and prolongs survival in alphaB-crystallin-based desmin-related cardiomyopathy. Proc Natl Acad Sci USA 2007;104:5995– 6000.
  • Moretti A et al. (2010) Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med 363:1397–1409.
  • Rajasekaran NS et al. Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. Cell 2007;130:427– 439.
  • Sun N et al. (2012) Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci Transl Med 4:130–147.
  • Vicart P et al. A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 1998;20:92–95.
  • Wang X et al. Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice. Circ Res 2001;89:84 –91.
  • Yazawa M et al. (2011) Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471:230–234.

STEM CELLS correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.