Vascular smooth muscle cells derived from iPSCs generated from a progeria patient’s skin cells. Green spots (concentrations of the protein calponin) are not seen in cells from healthy patients.
Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease that affects one in every 4–8 million newborns. Children with HGPS appear normal at birth, but eventually develop many symptoms associated with aging, such as skin wrinkles, growth retardation, osteoporosis (loss of bone mass) and atherosclerosis (hardening of blood vessels), within their first year of life. There is no known cure for HGPS, and few children with HGPS have ever reached adulthood as 90% of them die from complications, such as heart attack or stroke, at an early age.
Although HGPS seems to accelerate the aging process, remarkably the disease does not cause neural degeneration, diabetes, cancer or cataracts. It appears that HGPS mainly affects cells that make up the bone, cartilage, collagen, subcutaneous fat and blood vessels. Alan Colman and Colin Stewart at the A*STAR Institute of Molecular Biology and co-workers have now begun to understand the basis of the observed pathology through stem-cell technology.
The researchers obtained skin cells, known as fibroblasts, from two patients with HGPS. They transformed the fibroblasts into stem cells by injecting them with the standard ‘Yamanaka’s cocktail’ formula comprising transcription factors OCT4, SOX2, KLF4, and CMYC.
Stem cells derived in this way are called induced pluripotent stem cells (iPSCs) and have the ability to differentiate into almost any type of cell. The researchers used the iPSCs derived from HGPS patients to generate a variety of cell types, including neural progenitor cells, endothelial cells, fibroblasts, vascular smooth muscle cells (VSMCs) (pictured) and mesenchymal stem cells (MSCs).
Previous studies have shown that HGPS is caused by mutations in the gene LMNA. The mutated gene produces the mutant protein progerin, but exactly how progerin causes HGPS is unclear.
The researchers analyzed all their generated cell types and found that progerin levels were highest in MSCs, VSMCs and fibroblasts, and lowest in neural progenitors. Progerin-expressing MSCs and VSMCs had more DNA damage and nuclear abnormalities, and were more sensitive to stress and low-oxygen environment than normal MSCs and VSMCs.
MSCs are stem cells that can differentiate into bone cells, cartilage cells and fat cells, whereas VSMCs are cells that surround the larger blood vessels. The results therefore suggest that progerin may cause fragile bones, saggy skin and cardiovascular diseases partly by exerting toxic effects on those cell types that accumulate the most progerin and partly by depleting the number of stem cells available for cell replacement. The findings will help scientists develop new strategies to combat HGPS.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular Biology.
