Hutchinson-Gilford Progeria Syndorme, or childhood progeria, is a rare genetic disease that causes premature and accelerated aging, leading to early death in affected people in the first two decades of life. One of the most relevant pathological characteristics of the disease is the loss of smooth muscle cells in the arteries and arterial atherosclerosis, which in many cases causes myocardial infarctions or strokes that lead to death. The results of a new international research have described metalloprotease 13 as a new protein directly involved in this arterial vulnerability, which identifies it as a new target for the treatment of progeria. The study, which has been published in Nature Communications, has been led by University of Coimbra (Portugal) with the participation of the Neurovascular Diseases research group at Vall d'Hebron Institute of Research (VHIR).Childhood progeria is a genetic disease caused by a mutation in lamin A gene, which is part of the cell nucleus structure. With the mutation, progerin is generated. Progerin is a protein responsible for nuclear instability and subsequent disease-related cell damage. One of the most affected cells are smooth muscle cells that are part of the arteries, and especially those of the aorta, which are more vulnerable due to the mechanical stress produced by the strong blood flow to which they are subjected, which causes cardiovascular complications in these patients.In order to understand the process by which smooth muscle cells are lost in these large arteries, researchers from Coimbra used a microfluidic device with channels where cells were cultured and exposed to arterial shear stress. In this study, smooth muscle cells were generated from induced pluripotent stem cells (iPSC) obtained from fibroblasts from progeria patients. iPSCs allowed to have an unlimited source of vascular smooth muscle cells with the human mutation. Researchers used them to prove that progeroid cells had less resistance and detached from the chip more easily. "It was found that this process was largely mediated by metalloprotease 13 (MMP13), since it was highly expressed in progeroid cells and, furthermore, when this MMP was inhibited, there were fewer cells that detached and fewer cells with progerin", explains Dr. Anna Rosell, head of the Neurovascular Diseases research group at VHIR. Vall d'Hebron participation in the study mainly consisted in generating the appropriate in vivo model of the disease to validate the role of MMP13 in arterial damage and smooth muscule cells of the aortic arch. Specifically, they generated double mutant mice from existing transgenics to obtain animals with progeria that did not express MMP13, and controls with progeria and normal expression of MMP13. "We studied arteries of these mice and saw that those that did not express MMP13 reverted some characteristics of mice with progeria, specifically their aortic arch had more smooth muscle cells, which accumulated less progerin and their hair rate was more similar to that expected in healthy animals", indicates Dr. Rosell.The study also analyzed the effect of batimastat, a chemical inhibitor of metalloproteases that has been used in clinical trials for the treatment of some types of cancer. They found that the loss of muscle cells in the aortic arch was also lower. "The results indicate that MMP13 is a key protein for the malfunction of smooth muscle cells of the aortic arch and, therefore, could be a therapeutic target for the treatment of progeria", emphasizes Dr. Rosell. Thus, researchers propose to study the use of metalloprotease inhibitors for the treatment of progeria with a new therapeutic perspective through new clinical trials. Even so, the results have not shown an increase in life expectancy in mice with progeria, suggesting that metalloprotease inhibition should probably be combined with other drugs that reduce progerin accumulation and its toxicity.In parallel, the study shows that the stress model on progeroid smooth muscle cells carried out ex vivo with microfluidic chips and subsequent validation in in vivo models offers a new platform for the screening of new treatments. "It would allow us to test a large number of new candidate molecules for the treatment of progeria and, based on the results, choose with ones would have the best therapeutic potential in preclinical studies in animal models of the disease", adds Dr. Rosell.