An engineered blood vessel made from three cell types identified fibroblasts as a hidden contributor to childhood progeria, and DNA editing brought signs of disease close to normal
An engineered blood vessel made from three cell types identified fibroblasts as a hidden contributor to childhood progeria, and DNA editing brought signs of disease close to normal
A team from Duke University and the laboratory of David Liu, who developed DNA base editing, built the first three-layer engineered human blood vessel and reproduced the vascular disease seen in Hutchinson-Gilford progeria syndrome, a form of childhood progeria. Fibroblasts in the outer layer, which are usually absent from these models, increased inflammation, scar tissue formation, and vessel wall stiffness. Correcting the LMNA mutation with base editing brought almost all signs of disease back to healthy levels.
Hutchinson-Gilford progeria syndrome is caused by a rare mutation in LMNA. Cells produce a toxic protein called progerin, which accumulates in the nuclear envelope, distorts the nucleus, and impairs DNA repair, accelerating aging. Children with the condition almost always die in adolescence from severe atherosclerosis, a heart attack, or a stroke.
Laboratory models of this disease usually contain only the smooth muscle cells and endothelial cells of the inner arterial layers. They rarely include the outer layer, the adventitia, which contains fibroblasts, even though these cells renew connective tissue and regulate vascular tone. George Truskey’s group at Duke University was the first to build a vessel with all three layers. They used patient-derived stem cells to produce the endothelium and smooth muscle cells, then added an outer layer of genetically matched donor fibroblasts. Its gene activity more closely resembles that of a real artery than does the gene activity of two-layer models.
When the researchers built this vessel using cells from people with progeria, it reproduced more features of the disease than the two-layer version. Inflammation, collagen accumulation, and vessel wall stiffness increased, and smooth muscle cells began to die. These are the changes that lead to patients’ deaths.
The team tested causality directly. They corrected the LMNA mutation using base editing, which replaces a single DNA “letter” without cutting both strands, and built a three-layer vessel from the edited cells. Progerin disappeared, and most signs of disease returned to normal. Five years earlier, a single injection of the same editor had extended the lifespan of mice with progeria from 215 to 510 days. A year and a half earlier, the same laboratory had corrected a two-layer vessel without fibroblasts. The correction now reverses a wider range of abnormalities that became apparent only when fibroblasts were included.
By building vessels with different combinations of healthy and mutant cells, an approach unavailable in a living organism, the authors distinguished each cell type’s contribution for the first time. Smooth muscle cells containing progerin die and promote calcification and collagen accumulation. Inflammation increases only when progerin is present in both smooth muscle cells and endothelial cells. Fibroblasts containing progerin are the main source of IL-6 and TGFβ-1 signals, which trigger inflammation and fibrosis. A related pattern also appears in living mice: in a cell map of their aortas, smooth muscle cells resembled fibroblasts before dying. The three-layer vessel identifies the actual neighboring fibroblasts as the cells responsible.
Editing produced an incomplete recovery: the vessel’s overall gene activity remained closer to that of a diseased vessel than a healthy one. The likely explanation is the timing of the edits. Smooth muscle cells and endothelial cells were edited at the stem cell stage, before progerin was present. The fibroblasts, however, were collected as mature cells from patients and had already been affected by the disease before editing. A trace of the disease remains in the way their DNA is packaged, even after progerin is gone. Correcting the genetic cause can therefore leave the cells’ memory of the disease in place.
The authors also propose using this model to study other vascular diseases, including atherosclerosis and fibrosis unrelated to progeria.