The following is a summary of “Recapitulating primary immunodeficiencies with expanded potential stem cells: Proof of concept with STAT1 gain of function,” published in the April 2024 issue of Allergy & Immunology by Liu, et al.
Inborn errors of immunity (IEI) often lack specific disease models and personalized management strategies. Signal transducer and activator of transcription (STAT)-1 gain of function (GoF) is an example of an IEI with diverse clinical phenotypes, unclear pathomechanisms, and unpredictable responses to therapy. The limited availability of fresh samples for functional testing and research underscored the need for patient-specific ex vivo platforms. Using STAT1-GoF as a representative IEI, researchers, for a study, investigated the potential of patient-derived expanded potential stem cells (EPSC) as an ex vivo platform for disease modeling and personalized treatment.
EPSC was generated from individual STAT1-GoF patients, and STAT1 mutations were confirmed using Sanger sequencing. Functional testing, including STAT1 phosphorylation/dephosphorylation and gene expression, was conducted with or without Janus activating kinase inhibitors. Functional tests were repeated on EPSC lines with GoF mutations repaired by CRISPR/Cas9 editing.
EPSC were successfully reprogrammed from patients with STAT1-GoF and expressed pluripotent markers similar to controls, albeit with distinct morphological differences. Patient-derived EPSC recapitulated the functional abnormalities observed in index patients with STAT1-GoF, including STAT1 hyperphosphorylation and increased expression of STAT1 and its downstream genes (IRF1, APOL6, and OAS1) following IFN-γ stimulation. Treatment with ruxolitinib and baricitinib inhibited STAT1 hyperactivation in STAT1-GoF EPSC in a dose-dependent manner, whereas tofacitinib showed no effect. Corrected STAT1 phosphorylation and downstream gene expression were observed in repaired STAT1-GoF EPSC lines.
The proof-of-concept study demonstrated the potential of the patient-derived EPSC platform to model STAT1-GoF and potentially other IEIs. The proposed platform holds promise for researching, recapitulating, and repairing various IEIs in the future.
Reference: sciencedirect.com/science/article/abs/pii/S0091674923024119