The seeds of regeneration

Anyone who has owned a car or a house knows that unless you constantly maintain it and conduct repairs, it is not going to last very long. That’s true for our bodies as well. In fact, there is evidence to suggest that within many of our tissues and organs live a relatively small number of adult stem cells that can repair or replace tissues and parts of organs damaged by injury or disease. These cells, which may represent sentries remaining from our embryonic development, also play an essential role in what is termed “homeostatic maintenance” – keeping our organs in a constant state of health through renewal.

To scientists seeking new treatments for disease, these tissue-specific adult stem cells present several opportunities. For example, it may be possible to identify factors that stimulate the growth and activity of these cells so their role in the repair of damaged tissues can be enhanced. Another benefit could be derived from isolating these tissue specific stem cells and using them to generate cell lines that can be maintained in the laboratory, and used for screening new drugs for toxicity or effectiveness before they are tested in humans.

The Search is On

Organ tissues can be roughly organized into three categories: those that have many active tissue-specific stem cells, those that have very few or declining populations, and those that have none.

The blood system has perhaps the richest source of tissue-specific stem cells. Hematopoietic or blood-forming stem cells and mesenchymal stem cells that form bone, cartilage, and fat, can all be found in the bone marrow, a component of the blood system. Because of the relatively large number and active nature of the hematopoietic stem cells, it has been possible to use them to treat cancers and other diseases of the blood and immune system. The skin and gut similarly, are constantly renewing at a high rate.

In contrast to the blood system, skeletal muscle stem cells are much more rare and lose their ability to repair muscle injuries over time, as they decline in both number and function with age. However, identifying these tissue specific stem cells and studying what controls their capacity for regeneration could open the door for new treatments that encourage self-repair.

At the far end of the spectrum is the pancreas, which many scientists believe has no tissue-specific stem cell. This situation presents a particularly difficult challenge in developing treatments for diabetes – a disease where pancreatic beta cells are destroyed.

Niches in Dishes

How does a stem cell know when to kick into action and repair damaged tissues and organs? That’s a question that many scientists are asking, and some of the theories they are coming up with have been borrowed from the field of ecology. In an ecosystem, the survival and behavior of each organism is dependent on interactions with its environment or “niche.” It has been proposed that stem cells know when and how to act by communicating with their environment, including the surrounding cells. The “niche” normally keeps the stem cells in a balanced state of self renewal, perhaps splitting off specialized cells in regular intervals by an internal ‘clock.’ But when change occurs, the niche can activate stem cells, causing them to move to where they are needed and to differentiate into specialized cells to complete the repair.

Researchers are now working to reproduce stem cell niches in the laboratory. If the factors and conditions that control stem cell behavior can be isolated, the cells could be developed for therapeutic use, for screening new drugs, or for the creation of biomaterials that can replace complex structures within the body that can not be reconstructed by a simple infusion of stem cells.

The Stem Cell as Helper

In some cases, stem cells do not appear to be taking center stage in the repair and regeneration of tissue but are key players nonetheless. In the kidney, it was found that when the tubules used for drawing off waste fluids from the blood are damaged, it is the mature epithelial cells, not stem cells, which step in to rebuild the tissue. However, stem cells are thought to play a role in helping the epithelial cells to “de-differentiate” before they multiply and transform back into mature epithelial cells again.

Moving Forward on Multiple Fronts

Because not all tissue-specific stem cells are the same, scientists must employ different strategies depending on the organ or disease in question. Hematopoietic stem cells allow the blood system to constantly replenish itself throughout a person’s life. Therefore these cells are not only studied with the intent of increasing the efficiency of transplants and generating new cell-based therapies for blood diseases, but also so that their remarkable capacity for self-renewal can be modeled and applied to other organ systems.

In cases where there are few tissue-specific stem cells or those present are inactive, such as in skeletal muscle, the goal is to determine what factors will initiate or increase the level of their regenerative capacity. HSCI faculty are interested in understanding how to encourage replication of these small populations not only for therapeutic possibilities but also for use in screening and toxicology assays (see "Stem cells as tools" in this issue).

Our ability to grow both embryonic and adult stem cells now makes it possible to achieve both the quality and quantity of cells needed.

When an organ, such as the pancreas, does not have a tissue-specific stem cell, research is directed at how to stimulate replication of the mature cells, such as pancreatic beta cells, that have not been destroyed, or how to derive new beta cells from “unprogrammed” embryonic stem cells. The need to identify and characterize tissue-specific stem cells applies across organs, tissue types, and diseases. At the same time, it is important to understand the limitations of each stem cell type. Several HSCI faculty have engaged in many experiments to understand the specificity of tissue-specific stem cells. In other words, can a blood stem cell contribute to cardiac repair, or a skin stem cell to another organ? By and large, it seems that tissue-specific stem cells are in fact committed to producing cells within a particular tissue type. In many senses, this is an advantage for using these cells for tissue repair, as transplanted tissue-specific stem cells will already “know” which cells they should produce. However, this also means that attempts, some of which are even in clinical trials, to introduce cells of one type into a distinct organ system to effect repair are likely misguided. A better understanding of how stem cells contribute effectively to organ repair will depend increasingly on capable analytical tools such as in vivo cell imaging that can show where cells go, how they engraft, how they transform, and how they survive and procreate.