First things first…what are stem cells?
Stem cells can be divided into two major types: embryonic and adult. Embryonic stem cells, as the name suggests, can be found in the embryo. In the young embryo, called blastocyst, embryonic stem cells are found in the inner cell mass and are capable of generating all cells that will compose the future adult human. I, on the contrary, study the other kind of stem cells: adult stem cells. In adulthood, our bodies rely on stem cell function for our health. Our tissues are in constant renewal, as cells die within different organs and new cells replace those that are lost. The engineers behind this constant process of self-renewal are the adult stem cells. Two properties distinguish both kinds of stem cells from any other cell type found in our body: they can divide and give origin to other stem cells, self-renewal, and they can divide to generate different cell types with very different biological functions, differentiation.
Organs in the body have different needs in terms of renewal, and therefore depend differently on the activity of their unique stem cell populations. For instance, the skin is a highly dynamic tissue, where cells die and skin stem cells originate new skin cells at a fast-pace. This is in stark contrast with what happens in our brain or heart, where little tissue renewal is observed.
“Two properties distinguish stem cells from any other cell type found in our body: they can divide and give origin to other stem cells, but they can also divide to give rise to different cell types with very different biological functions”
Due to its nature, knowledge on how stem cell behavior is regulated is of great interest for regenerative medicine. Once better understood, stem cell function can be manipulated as a strategy to develop novel therapies for a wide range of diseases including Alzheimer’s disease, Parkinson’s disease, cancer, blindness, to name a few. Scientists like me are particularly interested in studying the tissue microenvironment in which adult stem cells are found, as it has been shown to be a crucial component for how stem cells behave.
So… adult stem cells are not found randomly in the body?
No, stem cells reside in specialized tissue compartments, within a microenviroment composed of complex networks of cellular and non-cellular cues that regulate adult stem cell behavior. When removed from their natural microenvironment, adult stem cells stop behaving normally and can lose characteristics that define them as stem cells, including the ability to self-renew. These microenvironmental anatomical entities are known as stem cell niches, a term coined by Dr Richard Schofield in the late 1970s (1). Stem cell niches provide a constant crosstalk between different cell types (stem and non-stem) via physical and chemical cues to define cell position and behavior. Just as the Portuguese saying claims: “Diz-me com quem andas, dir-te-ei quem és” (Tell me who you walk with, I will tell you who you are).
In the past few years, I have been studying the biological principles that define stem cell niches: how they are formed and maintained, and how perturbations of the dynamic interaction between their components can lead to disease. As mentioned previously, stem cells have a tremendous potential for regenerative medicine.
The study of their microenvironment, and how they behave in vivo, is a very important aspect to address in our journey to better understand and use these special cells.
Figure 1. A-C Standing mobiles by Alexander Calder. D-E Germline and intestinal stem cell niches of Drosophila.
What do animos from Alexander Calder have in common with stem cells?
What does the Beijing National Stadium or the French writer Émile Zola have in common? The same as the Lotus temple in New Delhi and Alberto Caeiro, one of the heteronyms of the famous Portuguese writer Fernando Pessoa? All of these are examples of artists inspired by nature. The converse is not so common, and examples of scientists inspired by art are more difficult to be found.
During a visit to the Seattle Art Museum I was introduced to the work of Alexander Calder and his inspiring mobiles. By watching these art pieces, my mind immediately wandered through how many commonalities one could find between these mobiles and stem cell niches. And suddenly, understanding and explaining how these anatomic entities behave became simpler.
Allow me to start by inviting you to appreciate the aesthetics of mobiles and stem cell niches. Although there is something common between all mobiles structures (see examples in Figure 1 A-C), they can be found in several different formats. The same happens with stem cell niches: biologically we place them all in the same category but the diversity of forms is as vast as the tissues in which they reside. Two examples of stem cell niches are found in Figure 1 D and E. These images are generated using proper laboratory techniques, where scientists label different cell types with fluorescent colors within biological tissues and photograph them using powerful microscopes. If you are an art lover and enjoy going to museums on a regular basis, perhaps you find similar appealing properties in these biological images as those expected from art pieces.
“Stem cells reside in specialized tissue compartments, within a microenviroment composed of complex networks of cellular and non-cellular cues that regulate adult stem cell behavior. (…) These anatomical entities are known as the stem cell niches.”
Stem cell niches are made of different ‘building blocks’. Note for example the blue cells in the stem cell niche of Figure 1 D; despite their small size and number, they are the most important cellular structure of this specific stem cell niche. They are the source of molecular signals that confer stem cell identity by generating and releasing self-renewing signals. Therefore, only cells immediately adjacent to the blue cells receive the appropriate cues and behave as stem cells (green cells forming a rosette structure around blue cells) – an ‘intelligent’ architectural strategy designed by nature. But, like the mobiles, there are multiple architecturally different stem cell niches. Thus, as this diversity is appreciated, there is an opportunity for another lesson to be learned about stem cell niches through its analogy with mobiles: avoiding blind generalizations.
Since they are diverse in their aspect and in the components that make them, scientists study stem cell niches separately. Although common aspects between different stem cell niches exist, it is wrong to assume, for example, that a specific diet, or a medicine, will impact all stem cell niches within our body in the same manner.
The analogy between mobiles and stem cell niches can be better understood when you watch mobiles in their equilibrium state – inside a room, mobiles pieces are not static, they move very slowly in response to small and sporadic air movements that do not lead to major alterations of the overall structure (see video below). But when exposed to a bigger perturbation, for example when you pull one of the pieces, or when a fan blows strongly on the mobile, you can see that the equilibrium state is now compromised and all pieces move at a fast pace as if in a ‘fight’ to keep its balance. Most times this ‘fight’ ends shortly after the perturbation is gone, and the mobile returns to its natural equilibrium state. I often use this example to explain one important property of stem cell niches: their dynamism. Stem cell niches transit through homeostatic (equilibrium) and challenging states. During homeostasis, cells that compose the stem cell niche show a coordinated, paced and unperturbed behavior. Not having a need to generate new cells, stem cells are often found quiescent: a biological regulated state where cells are found in a dormant state, not-dividing, waiting for a signal to become active. This quiescent state is very important for stem cells found in plants for example. It is the basis of seed dormancy and allows plants to preserve the capacity for growth, thereby circumventing unfavorable ecological conditions. Once conditions change, tissues need to be able to respond, for example, in injury situations like a cut in your skin or an infection in your stomach. These will be the analogous situations to the perturbation of mobiles equilibrium described previously. These sporadic situations induce a change on the dynamics of stem cells, calling them into action. They start to divide or divide more often in order to replenish cells that are lost as consequence of the damage done. Such response is highly regulated and, just like when you stop blowing on the mobiles and they go back to their equilibrium state, stem cell niches also normally resume to homeostasis when injury is resolved.
One last analogy that I would like to make is the relative importance of the different components to the overall structure. If you consider the mobile in Figure 1C, it seems likely that the consequences of removing the white piece will be minor when compared to the removal of the red one. For this prediction, I have considered mostly piece position, size and weight. In stem cell niches, the importance of different cellular and non-cellular components also varies significantly. Their importance depends on many factors similar to the mobiles, like their size and position, but also on others more complicated, like the chemical signals they secrete.
In this text, I have used mobiles to introduce to you the concept of stem cell niches where multiple components are assembled in an anatomical structure to serve specific biological functions. I have described the importance of both commonalities and differences found between different niches and have highlighted the dynamic nature of the niche. If you are not a scientist, I hope this has made you appreciate biology in an easier, reader-friendly manner. If you are a scientist, then I hope this has made you think about certain aspects of your research in a slightly different manner, and perhaps think about what artwork you would use to better explain your object of study.
Inspired by the work of Howard Gardner and his theory of Multiple Intelligences (2), I highly recommend the incorporation of art in science teaching, enabling students to better understand complex biological systems. Science teaching is often focused on making students memorize significant amounts of data, leaving an important aspect behind: critical thinking. Using art analogies will boost students’ creativity, and help them to pose relevant questions. Also, these comparisons should be more often used for science communication with the public in general.
P.S. The author would like to thank Sofia Cerqueira and Justin Voog for comments on the first draft of this text and Leanne Jones for everything she taught him about stem cells.
1. Schofield R: The relationship between the spleen colony-forming cell and the
haemopoietic stem cell. Blood Cells 1978, 4:7–25.
2. Howard Gardner, Frames of Mind: The Theory of Multiple Intelligences, Basic Books, 1983
Luis Pedro Resende is a research associate at i3S (Instituto de Investigação e Inovação em Saúde). He is also the President of the GABBA alumni association, ATG – All Time GABBAS
Edited by: Tiago Marques (Section Editor), Cecilia Mezzera (Page Editor), Ivo Marcelo (Page Editor).
Image credit: Calder Foundation (Figure 1A-C), Luis Pedro Resende (Figure 1D-E)