Progeria on a chip

Organ-on-a-chip created to study premature aging

Oleg Lischuk, N+1

An international group of scientists has developed an artificial organ that allows us to find out how vascular cells react to their contractions are normal and in diseases. With his help, they found out that in one of the genetic diseases accompanied by premature aging (Hutchinson-Guilford progeria), mechanical stretching of cells leads to their inflammation. The study report is published in the journal Small (Ribas et al., Biomechanical Strain Exacerbates Inflammation on a Progeria-on-a-Chip Model).

Hutchinson-Guilford progeria is an extremely rare congenital disease (no more than 80 cases worldwide) in which, due to a gene mutation, a defect in the lamin A protein, which is part of the cell nucleus envelope, occurs. This leads to a violation of DNA repair, other biochemical defects and, as a consequence, to rapid aging of the body, which begins in childhood. Such patients are stunted in growth, they have a deformed skeleton, wrinkled skin, atrophic subcutaneous tissue, metabolic disorders, myocardial damage and atherosclerosis develop rapidly. The average life expectancy is 13 years, the cause of death, as a rule, is cardiovascular diseases.

The cells of the vascular walls are most susceptible to accelerated aging, which are constantly expanding and contracting under the influence of pulse waves, and if normally smooth muscle cells of vessels stretch by nine percent, then in pathology this indicator can reach up to 15 percent. What role such a dynamic environment plays in cell aging has not been sufficiently known until now. Animal models are poorly suited for studying this process, since the conditions in the vessels and the molecular changes associated with aging do not fully correspond to human ones.

To understand this issue, the staff of the Massachusetts Institute of Technology with colleagues from the USA, Portugal, the Netherlands and France have created an organ-on-a-chip that simulates the natural movements of the vascular wall in various conditions. The polydimethylsiloxane device measures 40×18 millimeters and consists of two chambers separated by an elastic partition. One of the chambers contains a straight channel measuring 25 × 1 millimeter, coated with fibronectin for cell adhesion and acting as a blood vessel through which nutrient fluid is passed. The other is a closed cavity in which negative pressure is cyclically created in the range from 0 to 50 kilopascals, which simulates contractions and distensions of the vessel.

The vessel-on-a-chip device (here and below are the drawings from the article in Small)

Scientists populated the "vessel" with smooth muscle cells differentiated from induced pluripotent stem cells, which were obtained from fibroblasts of healthy people and patients with progeria, and then subjected them to cyclic stretching. After 24 hours, the cells began to line up perpendicular to the direction of the mechanical force and connect with each other, as in a living blood vessel.

It turned out that in healthy cells, both physiological and pathological stretching led to a decrease in the level of lamin A. In contrast, in the cells of patients with progeria, physiological stretching led to a slight increase in the level of the defective variant of this protein, progerin, and pathological stretching led to a decrease in the expression of progerin and an increase in the normal form of lamin A.

Growth of healthy (from above) and defective vascular smooth muscle cells
without dynamic loads and with pathological stretching

In addition, it turned out that the accumulation of progerin leads to an increase in the mechanosensitivity of smooth muscle cells and, as a consequence, an inflammatory response in them. In particular, in cells with a defective gene, cyclic 16% stretching caused increased expression of inflammatory markers IL6, IL1B and JUN, a marker of hypertensive vascular damage CAV1, as well as an increase in the number of DNA damage, which is not observed when cultured without mechanical stress and in healthy cells. In an experiment with an organ-on-a-chip, scientists managed to reverse a similar inflammatory response in defective cells with the anti-atherosclerotic drug lovastatin and the experimental farnesyltransferase inhibitor lonafarnib, which suppresses the synthesis of progerin.

"The created platform is suitable for studying the role of biomechanics in vascular biology, in particular in the conditions of vascular diseases and aging, while facilitating the search for new drugs and targets for therapy," the authors write.

Recently, scientists have managed to reverse aging and prolong the life of mice with a progeria model by temporarily "turning on" transcription factors that convert mature cells into stem cells (the so-called Yamanaki factors named after the Nobel laureate who developed the technology for producing induced pluripotent stem cells).

Portal "Eternal youth" http://vechnayamolodost.ru  07.03.2017