Using Direct Conversion of Cells to Investigate the Behavior of Aging Tissues

The process of reprogramming used to produce induced pluripotent stem cells erases many of the marks of aging in cells taken from old tissues, such as epigenetic changes and declining mitochondrial function. This may prove to be the basis for therapies based on reprogramming, but it is also very inconvenient for researchers who want to study how old cells and tissues behave in detail. Thus scientists here use a process of direct conversion, programming one cell type to become another without inducing a stem cell state, in order to retain the features of old tissue. That allows the identification of differences between old and young cellular metabolism, and run initial tests of potential interventions in cell cultures.

Research into aging vasculature has been hampered by the fact that collecting blood vessel cells from patients is invasive, but when blood vessel cells are created from special stem cells called induced pluripotent stem cells, age-related molecular changes are wiped clean. In 2015, however, researchers showed that fibroblasts could be directly reprogrammed into neurons, skipping the induced pluripotent stem cell stage that erased the cells' aging signatures. The resulting brain cells retained their markers of age, letting researchers study how neurons change with age. In new work, researchers applied the same direct-conversion approach to create two types of vasculature cells: vascular endothelial cells, which make up the inner lining of blood vessels, and the smooth muscle cells that surround these endothelial cells.

The researchers used skin cells collected from three young donors, aged 19 to 30 years old, three older donors, 62 to 87 years old, and 8 patients with Hutchinson-Gilford progeria syndrome (HGPS), a disorder of accelerated, premature aging often used to study aging. The resulting induced vascular endothelial cells (iVECs) and induced smooth muscle cells (iSMCs) showed clear signatures of age. 21 genes were expressed at different levels in the iSMCs from old and young people, including genes related to the calcification of blood vessels. 9 genes were expressed differently according to age in the iVECs, including genes related to inflammation.

To test the utility of the new observations, the researchers tested whether blocking BMP4 - which had been present at higher levels in smooth muscle cells developed from people with HGPS - could help treat aging blood vessels. In smooth muscle cells from donors with vascular disease, antibodies blocking BMP4 lowered levels of vascular leakiness - one of the changes that occurs in vessels with aging. The findings point toward new therapeutic targets for treating both progeria and the normal age-related changes that can occur in the human vascular system.