Structure Variations and 3D Genome Disruption: Implications in Safety of hPSC-Based Cell Therapy

Area of Science:

• Genomics
• Stem Cell Biology
• Regenerative Medicine

Background:

• Human pluripotent stem cells (hPSCs) hold great promise for regenerative medicine due to their self-renewal and differentiation capabilities.
• However, genetic instability, particularly structural variants (SVs), acquired during in vitro culture poses significant safety concerns for clinical applications.
• These SVs can compromise differentiation efficiency and elevate tumorigenic risk.

Purpose of the Study:

• To explore the causal axis linking SVs, 3D genome disruption, and the safety of hPSC-based therapies.
• To elucidate the mechanisms by which SVs impact hPSC safety and therapeutic potential.
• To provide insights for developing improved quality standards for hPSC products.

Main Methods:

• This review systematically examines existing literature on SVs in hPSCs.
• It focuses on the impact of SVs on the three-dimensional (3D) genome architecture.
• The review analyzes how 3D genome alterations lead to pathogenic rewiring of gene regulatory elements.

Main Results:

• SVs critically disrupt the 3D genome architecture in hPSCs.
• This disruption leads to aberrant enhancer-promoter interactions, such as enhancer hijacking and enhancer loss.
• These changes can aberrantly activate oncogenes or silence tumor suppressors, even without copy number variations.

Conclusions:

• 3D genome disruption is a key mechanism explaining SV-driven tumorigenic potential and impaired differentiation in hPSCs.
• Understanding the SVs-3D genome disruption-safety axis is crucial for advancing hPSC-based regenerative medicine.
• This framework offers actionable insights for establishing rigorous quality control measures for clinical-grade hPSCs.