30 March 2015

Lungs in a test tube

Artificial lung

Alexandra Bruter, <url>American scientists managed to create a miniature artificial lung without using donor organs (Dye et al., In vitro generation of human pluripotent stem cell derived lung organoids // eLife, 2015).

Such a lung cannot be transplanted to anyone yet, but this is already a great progress towards the creation of artificial three-dimensional organs.

Until now, if a person's organ fails, he begins to have big problems. For some time, for example, in case of kidney failure, dialysis allows you to hold out, but the quality of life is greatly reduced. In fact, only a donor organ transplant can help. You can only transplant an organ that the donor does not really need: either it is a paired organ, or it is a recently deceased donor. Recently, a third option appeared, when the organ was simply no longer needed by the donor: women who did not have a uterus were transplanted into the uterus of elderly relatives who already had children. In all these cases, it is still necessary to solve the problem with the recipient's immune response against the donor organ. In practice, this means that only a related transplant can be carried out quickly if there is a suitable relative. In all other cases, the patient will have to wait a long time and hope for a miracle.

It is much easier and, as a result, bone marrow transplantation occurs more often. The donor is in no danger in this case, and the only requirement remains tissue compatibility. The simplicity of bone marrow transplantation is associated with two aspects: firstly, blood stem cells themselves multiply rapidly, and secondly, the bone marrow does not have such a complex three-dimensional structure as, for example, the lungs or liver.

The three-dimensional structure of each organ is formed once, during embryonic development. Different organs can regenerate and self-renew to varying degrees, patching minor injuries, but human organs cannot regenerate entirely. The body cannot grow a new kidney by itself. There are a lot of molecular signals involved in the regulation of embryonic development, which cells exchange with each other, and the rest of the body – with a group of cells that should form an organ. Not all of these signals have been deciphered by scientists and can be simulated in a test tube, and without them it is impossible to get a new functional organ, no matter how many stem cells you have.

As a half-measure, a trend has recently been developing related to the destruction of cells in donor organs and the colonization of the remaining intercellular matrix with the recipient's own cells. This makes any donor suitable, even if he is not a relative at all, and besides, he treated his organs badly during his lifetime.

The task of learning how to grow organs or their functional elements without resorting to donor organs looks much more ambitious.

The functional element of the lung is a tube (bronchiole) and a pouch (alveolus) located at its end. Air flows through the trachea into the bronchi, the bronchi branch, and the thinnest branches at the ends are the bronchioles. Blood vessels approach the surface of the alveoli, and gas exchange takes place there. All this almost fractal construction is needed to maximize the gas exchange area.

It was this "monomer" of the lung, a tube with a pouch at the end, that American scientists managed to grow. In embryogenesis, the lungs begin to develop in the third week after fertilization as outgrowths from the anterior (upper) part of the future digestive tract. It is an organ of predominantly endodermal origin. Scientists have found a way to turn pluripotent stem cells into endoderm some time ago, for this it is enough to add activin A to the cells. To direct the cells to the further path of transformation into lung cells, the authors of the work had to pick up a number of activators and inhibitors of various signaling pathways regulating cell growth and differentiation.

As a result, they turned out to have spheroids consisting of the same cell types as the alveoli, and airways resembling bronchioles. The resulting structures are most similar to the lungs at a certain stage of embryonic development. Scientists did not provide the cultured cells with an additional matrix or any other external structures to help spatial organization. They controlled all processes by activating and inhibiting signaling pathways.

This is what an organoid looks like in a conventional microscope…


...and its section under fluorescence microscopy
next to the section of adult lung tissue – they are quite similar in structure.
Images from the University of Michigan Medical School press release
Scientists coax stem cells to form 3-D mini lungs – VM.

Under laboratory conditions, the organoids lasted about 100 days. It is too early to say that scientists have received organs suitable for transplantation, but this is already a significant step forward. Even now, the obtained organoids can be used to study the features of embryonic development of the lungs and the effects of potential drugs.

Portal "Eternal youth" http://vechnayamolodost.ru30.03.2015

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