Stem cell bioengineering
Ali Khademkhoseini, Post-Science
Stem cells have been the most important topic of scientific research for several years now: they allow for a constant supply of cells needed to solve various medical problems. To date, many new types of stem cells have been discovered, with much attention being paid to their biological characteristics. However, more and more researchers have recently realized that, although the biological component is important, it is necessary to develop engineering methods to control the behavior of cells.
Under normal conditions, stem cells are located in the body, that is, in an active environment that sends cells a large number of signals and thus indicates how to behave. The question is how we can manage this environment. Many different works on this topic have been published recently. Let's say we want to change the way cells interact with each other. Instead of just putting them in a Petri dish and observing, we can resort to engineering methods.
During one of our work, we placed cells in microstructures that allowed us to control how these cells come together in groups, that is, with the help of such microstructures, we can control how cells interact with each other and combine into clusters. As we know, it is very important how many neighboring cells each stem cell sees around itself, and with the help of engineering systems we can control this with great accuracy.
Part of the work we have done, for example, shows that if there are a lot of embryonic stem cells somewhere, they begin to "communicate" with each other and create formations that are likely to become heart cells. When their number is small, they are more likely to differentiate into blood vessel cells. If we look at the reasons and study the biological side of such engineering, it becomes clear: thanks to the systems created by us, cells feel a different environment around them, communicate with each other using different signals and, based on how many neighbors are nearby, are transformed either into heart cells or blood vessel cells. This is one example.
There are other ways to apply engineering approaches to stem cells. For example, the question of how all components of a biological system, whether genes or proteins, affect cells is becoming increasingly important. We receive a large amount of data from proteomic and genomic studies, and to them we can apply the developments that are used to create electrical circuits. We use the same concepts to logically understand the diversity and complexity of the information that comes to us. As a result, we have an approach in which the knowledge of computational sciences and computational engineering is used to control the behavior of structures inside the cell. As in electrical engineering, we can operate with diagrams, a time scale, switching on and off various elements – only in relation to the bioengineering scheme of genes in stem cells. These are two examples: in one, engineering work takes place inside the cell itself, in the other, it helps to control the behavior of many cells from the outside.
Stem cell engineering and biology can develop in other ways. Thanks to bioengineering, we know that using various methods it is possible to control how molecules are released into the environment. You can take decomposable particles and encapsulate biological molecules, such as various kinds of signaling proteins and other kinds of hormones, and then be able to slowly release them from these particles. This approach is also applicable to stem cells. If you take a single cell or an entire group and supply them with growth factors in the right way, you will manage their activities. It is possible to design these particles so that molecules of one kind are released very quickly, and the other – very slowly. As a result, the gene expression profile will be the same as in normal development – in conditions when signals consistently tell the cell what to do. That is, it is possible to recreate exactly the same biological environment.
Other approaches include using different types of peptides or proteins to create materials that will determine the behavior of the cell. The behavior will depend on the release of molecules by a material, for example, containing a platelet growth factor, or on its certain mechanical properties: hard materials can give the impression of a bone environment to the cell, and soft materials can imitate a fatty environment. So we can send signals to the cell about what to do and how to change.
There are still ways how an artificially created cellular environment can guide stem cells. Mesenchymal stem cells can be used to create microfluidic systems with an endothelial layer. If you put a solution on them, these mesenchymal stem cells will literally roll through the blood vessels. We will see how mesenchymal cells interact with blood vessels and how they penetrate into tissues. All this happens in an artificial environment, which allows you to learn more about the nature of these cells and what types of molecules are needed to hold cells in certain places or make them migrate. This method can be useful in creating a source of cells that can be transplanted directly into the blood. The cells will then spread throughout the body and, having found the location of the defect or disease, will move to it. So you don't need to create a tissue – you can just create a cell and examine it to figure out how to make it find certain tissues.
These are some points illustrating how engineering methods are applied in stem cell biology. They help to understand their nature, design their environment, investigate how external signals affect genetic differences within cells, and simulate different situations. Of course, this is only part of the examples, but imagine others. For example, an engineering approach can be used to visualize the cells in the body in the appropriate microenvironment: if they are labeled, you can track how they move to the bone marrow and exit. There are a lot of such opportunities, and they exist precisely thanks to the development of engineering technologies.
I think there is a lot of potential in this. Since hematopoietic stem cells were first discovered, the fields of engineering and stem cell research have been actively interacting with each other. Attempts were immediately made to extract bone marrow and reproduce it artificially so that bone stem cells could be obtained in large quantities and transplanted to patients. A lot of work has been done to develop bioreactors for growing stem cells, increasing their number and transplantation.
Work in this field has been increasingly converging for many decades with research on what cells react to, how they see their environment and how we can optimize it. This applies to the study of certain aspects of the intercellular environment, to the general understanding of cell behavior, and to the use of computer technology. Combining all these things, it is possible to develop effective methods of treating diseases. Some of them, such as, for example, bone marrow transplantation, have already been carried out, and, for example, methods of working with induced pluripotent stem cells and their application in personalized medicine are yet to be done.
One of the main problems that scientists have found in stem cells is that embryonic stem cells and undifferentiated stem cells are so undeveloped that they can form tumors if they do not differentiate into mature cells. This has been observed many times during the injection of embryonic stem cells into the bodies of laboratory mice. If embryonic stem cells don't differentiate properly, they do form tumors. How can engineering be applied in solving this problem? I think it depends a lot on how to use engineering methods to differentiate cells. If cells are exposed to an environment that invariably tends to differentiate cells into different types, the number of undifferentiated cells will be minimized, and therefore the chance of a tumor will be significantly reduced. If all cells see a homogeneous environment around them in a bioreactor or a microreactor, then they will behave in concert, each of them will differentiate in the same way.
There are other engineering methods by which it will be possible to isolate tumor cells from fully differentiated cells. For example, they can be used to detect something: you can stain cells and thus check them for maturity markers, revealing which of them may be mature and which are not. Thus, with the help of microfluidic systems, tumor cells can be captured and separated from differentiated ones.
There are many technologies that can help get rid of tumor cells or remove the remaining ones with general cell differentiation. We know that in nature, the cells that lead to the formation of an organism have the same properties as embryonic stem cells. But in nature, due to environmental control, all cells differentiate properly and reach the necessary stages of development, while in vitro, if undifferentiated cells do not do this, they form populations that can turn into tumors. So the use of the same natural biological principles is necessary in conjunction with engineering methods so that it is possible to apply these principles to cells and prevent them from becoming tumor.
About the author:
Ali Khademhosseini – Full Professor of Medicine and Health Sciences and Technology Harvard-MIT Division of Health Sciences and Technology Harvard Medical School, Brigham & Women's Hospital
Portal "Eternal youth" http://vechnayamolodost.ru
28.03.2016