Loss of 18q Alters TGFβ Signalling Affecting Anteroposterior Neuroectodermal Fate in Human Embryonic Stem Cells

Area of Science:

• Stem cell biology
• Developmental biology
• Genetics

Background:

• Chromosomal abnormalities in human pluripotent stem cells (hPSCs) can affect their differentiation potential.
• Acquired genetic alterations during cell culture are a concern for hPSC applications.

Purpose of the Study:

• To investigate the impact of specific chromosomal abnormalities on hPSC differentiation into retinal progenitor cells.
• To identify the molecular mechanisms underlying impaired differentiation in hPSCs with complex karyotypes.

Main Methods:

• Comparative analysis of hESCs with and without chromosome 18q loss.
• Time-course gene-expression analysis during spontaneous differentiation.
• Single-cell RNA sequencing (scRNA-seq).
• Chemical modulation of TGFβ signaling pathways.

Main Results:

• hESCs with chromosome 18q loss exhibited diminished differentiation into retinal progenitor cells.
• These variant cell lines showed poor anterior neuroectoderm specification and inadequate cell pigmentation.
• Dysregulation of TGFβ signaling was observed during the differentiation of variant hPSCs.
• Imbalances in TGFβ signaling were identified as the cause of improper anteroposterior neuroectodermal fate commitment.

Conclusions:

• Loss of chromosome 18q in hPSCs compromises retinal progenitor cell differentiation.
• TGFβ pathway dysregulation is a key factor in the observed differentiation defects.
• Understanding these genetic and signaling alterations is crucial for improving hPSC-based therapies.