Elevated Senescence Markers in Developing Trisomy 21 Human Lungs

Area of Science:

• Genetics
• Developmental Biology
• Cellular Biology

Background:

• Human chromosomal anomalies, such as trisomies, significantly impact gene expression and lead to various cellular and organ phenotypes.
• Increased cellular senescence (SEN) and oxidative stress are emerging concerns in trisomic conditions.

Purpose of the Study:

• To investigate cellular senescence, senescence-associated secretory phenotype (SASP), and oxidative stress in human fetal lung tissues and fibroblasts with trisomy 13, 18, and 21.
• To establish the relationship between trisomy and these cellular stress markers during prenatal lung development.

Main Methods:

• Analysis of human fetal lung tissues and primary fibroblasts from trisomy 13, 18, and 21.
• Telomerase associated foci (TAF) staining for DNA damage.
• RT-qPCR for SEN and SASP marker gene expression (CDKN2B, IL-6, CXCL8, CDKN2A).
• γ-H2AX staining for DNA damage.
• Assessment of reactive oxygen species (ROS) using MitoSOX and CellROX.

Main Results:

• DNA damage (TAF, γ-H2AX) was observed in T21 and T18 lungs, with γ-H2AX upregulated across all trisomies, especially T21.
• Trisomy 21 (T21) and T18 lungs showed increased SEN marker CDKN2B and SASP markers IL-6 and CXCL8.
• Trisomy 13 (T13) lungs exhibited CDKN2A upregulation without significant SASP changes.
• T21 fibroblasts showed elevated SEN markers, P21 expression, and increased ROS levels.
• Fibroblasts from T13 and T18 also showed increased γ-H2AX positive cells.

Conclusions:

• This study presents the first evidence linking cellular senescence and trisomy anomalies during prenatal human lung development.
• Trisomy 21 demonstrates a significant association with elevated senescence markers, DNA damage, and oxidative stress in developing lung tissue.
• The findings highlight potential cellular mechanisms underlying the phenotypic consequences of trisomies in lung development.