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Generation of a transgenic pluripotent stem cell line expressing MMACHC protein harbouring the renal 2 thrombotic
Zhiqi Zhou1, Xiao'e Zhang2, Cuilan Hou3
1Department of Pathology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China.
Abstract:
Mutations in the MMACHC (metabolism of cobalamin associated C) gene are associated with cobalamin C disorder and have been reported in infants with renal thrombotic microangiopaopathy (TMA). The pathophysiology underlying these mutations and their role in causing endothelial damage remains elusive. We generated a transgenic pluripotent stem cell (iPSC) line expressing MMACHC protein harbouring the renal 2 thrombotic microangiopapathy-causing mutation (p.Q27R). The iPSC exhibits a typical stem cell morphology, expresses pluripotency markers, and displays a normal karyotype. The iPSC line provides a valuable platform for exploring the pathogenesis of endothelial injury induced by metabolism-mediated TMA and for screening drugs to reduce endothelial damage.
Insights
Mutations in the MMACHC gene cause cobalamin C disorder and renal thrombotic microangiopathy (TMA). A new iPSC model of this mutation aids in studying endothelial damage and testing therapies for TMA.
Area of Science:
- Genetics
- Stem Cell Biology
- Nephrology
Background:
- Mutations in the MMACHC gene are linked to cobalamin C disorder.
- These mutations have been observed in infants with renal thrombotic microangiopathy (TMA).
- The precise mechanisms causing endothelial damage in these cases are not fully understood.
Purpose of the Study:
- To create a cellular model for investigating the pathophysiology of MMACHC mutations in TMA.
- To establish a platform for screening potential therapeutic compounds.
Main Methods:
- Generation of a human induced pluripotent stem cell (iPSC) line.
- Engineering the iPSC line to express MMACHC protein with a specific TMA-associated mutation (p.Q27R).
- Characterization of the iPSC line for pluripotency markers, morphology, and karyotype.
Main Results:
- A functional iPSC line expressing the MMACHC p.Q27R mutation was successfully generated.
- The generated iPSC line maintained typical stem cell characteristics, including morphology, pluripotency marker expression, and a normal karyotype.
- This iPSC line serves as a viable model for studying TMA pathogenesis.
Conclusions:
- The developed iPSC line is a valuable tool for understanding how MMACHC mutations lead to endothelial injury in TMA.
- This model facilitates the screening of drugs aimed at mitigating endothelial damage in cobalamin C disorder-related TMA.
