Old, leaky blood vessels modeled via direct reprogramming of skin cells

When collecting tissue samples requires invasive procedures, devising a model for aging tissue can be difficult. This is the case for cardiovascular tissue. Although vascular cells can be generated through the reprogramming of skin cells, this approach puts the cells in an embryo-like state. That is, this approach erases the markers of aging. However, there is another possibility: direct reprogramming. It bypasses embryonic conditions and leaves aging markers intact.

Direct reprogramming was previously used in this way. Back in 2015, soak lab-based researchers show that fibroblasts can be directly reprogrammed into neurons, skipping the induction step of pluripotent stem cells, which erases the signs of cell senescence. did. The brain cells obtained carry an age marker and researchers were able to study how neurons change with age.

In a new study, scientists from the Salk Institute, led by Dr. Martin Hetzer, used direct conversion to create two types of vascular cells. Scientists started with fibroblasts collected from donors of various ages and patients with Hutchinson-Gilford progeria syndrome (HGPS), a disorder of accelerated premature aging. Applying direct conversion, scientists generated induced vascular endothelial cells (iVEC) and smooth muscle cells (iSMC). And scientists were able to model vascular aging and HGPS in vitro.

The details of this work appeared in the September 8th issue eLifeIn an article titled,Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and Hutchinson-Gilford progeria syndrome.. The “defects” mentioned in the article titles seem to correspond to therapeutic targets.

“IVEC derived from an old donor GSTM1 And PALD1, Genes associated with oxidative stress, inflammation, and endothelial junction stability as markers of vascular aging,” the author of the article wrote. “We discovered that iSMCs from HGPS donors overexpress bone morphogenetic proteins (BMP)-4, which plays an important role in both vascular calcification and endothelial barrier damage observed in HGPS. “

“Functional assay performed on PALD1 KD VEC showed restoration of vascular permeability,” they continued. “In addition, targeting BMP4 with blocking antibodies may restore vascular barrier function in vitro, which may be a future therapeutic strategy to limit HGPS cardiovascular dysfunction.”

In essence, this study has provided clues as to why blood vessels tend to leak and harden as they age. In addition, we have identified potential targets for new drugs aimed at slowing the aging of vascular cells.

“The vasculature is very important for aging, but its effects have been underestimated because of the difficulty in studying how vascular cells age,” said Sooke, vice president and vice president of the paper. Hetzer, Chief Scientific Officer, said.

Most knowledge about how vascular cells age is obtained by observing how the blood vessels themselves change over time. Veins and arteries lose their elasticity and become thickened and hardened. These changes may contribute to increased blood pressure and an increased risk of heart disease with age.

In the current study, 21 genes, including those associated with vascular calcification, were expressed at varying levels in iSMC in men and women of all ages. Nine genes, including those associated with inflammation, were differentially expressed in iVEC depending on age. In HGPS patients, some genes reflected the same pattern of expression normally seen in older people, while others were unique.

In particular, the levels of BMP-4 protein, known to play a role in vascular calcification, were slightly higher in aged cells than in young cells, but much higher in smooth muscle cells in patients with progeria. It was This suggests that proteins are especially important in promoting aging.

“One of the greatest theoretical implications of this study is to study one patient longitudinally during aging or during the course of treatment, how it’s vasculature is changing, and how I know now that I can study what can be targeted to.” Simone Bersini, PhD, Salk Postdoctoral Fellow and co-lead author of this paper.

“It’s one of the first people to use this technique to study aging of the vascular system,” said Dr. Roberta Schulte, coordinator of the Hetzer Institute and co-author of the paper. “There was the idea of ​​developing both of these cell types from fibroblasts, but we tailored the technology to meet our needs.”

“By repeating what was done in neurons, we have demonstrated that this direct reprogramming is a powerful tool that can be applied to many cell types to study the aging mechanism of all other types of human tissue.” Hetzer added.

Hetzer’s team plans future work to investigate the precise molecular mechanisms by which some of the genes found to change with age control the changes found in the vasculature.