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Patient-specific hiPSC-Podocytes as an in vitro model of genetic FSGS
Victoria Rose1, Denise Fink1, René Krüger1
1Department of Nephrology, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
Abstract:
Mutations in podocyte-specific genes are associated with genetic focal segmental glomerulosclerosis (FSGS), yet the potential for targeted treatments remains uncertain. Therefore, patient-specific models are essential for understanding cellular phenotypes, identifying personalized therapies, and avoiding ineffective treatments. This study utilized patient-specific human induced pluripotent stem cell (hiPSC)-Podocytes to investigate cellular phenotypic and functional alterations associated with genetic FSGS in vitro. HiPSC-Podocytes were generated from a patient with a mutation in the inverted formin 2 (INF2) gene, who showed a partial clinical response to steroid treatment. Compared to healthy donor-derived hiPSC-Podocytes, the patient-specific hiPSC-Podocytes exhibited decreased protrusion length, reduced levels of actin-associated markers, and alterations in INF2 protein levels. Additionally, actin filaments were disrupted, characterized by increased actin depolymerization. Next to the actin-modulating agent Bis-T-23, the steroid Solu-Decortin H (SDH) improved the actin cytoskeleton in the patient-specific cells, which aligned with the patient's partial response to steroids. This underscores the importance of personalized treatment strategies based on specific cellular responses in genetic FSGS.
Insights
Patient-specific stem cells reveal how inverted formin 2 (INF2) gene mutations cause focal segmental glomerulosclerosis (FSGS). Treatments targeting actin cytoskeleton may offer personalized therapies for genetic kidney disease.
Area of Science:
- Nephrology
- Genetics
- Cell Biology
Background:
- Mutations in podocyte genes cause focal segmental glomerulosclerosis (FSGS), a leading cause of kidney failure.
- Understanding cellular phenotypes is crucial for developing targeted therapies for genetic FSGS.
- Patient-specific models are essential for personalized treatment strategies.
Purpose of the Study:
- To investigate cellular and functional alterations in patient-derived induced pluripotent stem cell (hiPSC)-Podocytes with an inverted formin 2 (INF2) gene mutation.
- To assess the in vitro response of these cells to potential therapeutic agents.
- To correlate in vitro findings with clinical responses to guide personalized treatment.
Main Methods:
- Generation of hiPSC-Podocytes from an FSGS patient with an INF2 mutation.
- Comparison of patient-derived hiPSC-Podocytes with healthy donor-derived cells.
- Analysis of cellular morphology, actin cytoskeleton dynamics, and INF2 protein levels.
- Assessment of cellular response to an actin-modulating agent (Bis-T-23) and a steroid (Solu-Decortin H).
Main Results:
- Patient-specific hiPSC-Podocytes showed reduced protrusion length and altered actin cytoskeleton.
- Disrupted actin filaments and increased actin depolymerization were observed.
- INF2 protein levels were altered in patient-derived cells.
- The steroid Solu-Decortin H improved the actin cytoskeleton in patient-specific cells, mirroring the patient's partial clinical response.
Conclusions:
- Patient-specific hiPSC-Podocytes accurately model cellular defects in genetic FSGS.
- In vitro drug screening can predict clinical responses to therapies.
- Targeting the actin cytoskeleton holds promise for personalized treatment of INF2-related FSGS.
