Tuesday, 21 June 2011

Everyone loves stem cells

Stem cells have been THE hot topic for a number of years now. In theory, stem cells can be turned into any other cell type and could therefore be used to repopulate a damaged organ with healthy, normal cells. Sounds cool. "Stem cell" refers to a number of different cell types, some can become any cell in the body and some can become only a small subset of cells. Bone marrow, which contains blood stem cells, has been successfully used to repopulate blood after chemotherapy since the 1950s. Half a century later, some recent papers suggest that stem cells could also be used to repopulate damaged hearts and livers, but there have also been some troubling reports about the nature of stem cells, particularly induced pluripotent stem cells.

Stem cells come in three flavours: embryonic stem cells (ES cells), induced pluripotent stem cells (iPSCs), and resident stem cells. ES cells are more of a research tool than a potential therapeutic tool. They can be used to study the normal processes which turn a stem cell into all the different cells in the body. They have their much-debated ethical pitfalls, and ES research continues to be plagued by government restrictions and the threat thereof. The advantage of ES cells is that they can be turned into literally any cell, whereas iPSCs and resident stem cells are more restricted. An iPSC cell might become a heart or liver cell, but not a brain cell. The downfall of ES cells is immune incompatibility. When foreign cells are injected into a patient, the patient's immune system will recognize them as foreign and attack them. Bone marrow and other organ donations are matched as closely as possible to the patient, but even then most patients are on immunosuppressant drugs to prevent rejection. ES cells, since the embryo is destroyed in order to get the cells, will never be genetically identical to a prospective patient and immune incompatibility will always be an issue.

iPSCs, on the other hand, are made from the patient's own cells so shouldn't be rejected. Cells taken from a person's skin (for example) are grown in dishes and turned into iPSCs through a variety of different protocols including genetic modification or drug treatment. Recently, cells from a mouse's tail have been turned into iPSCs and used to repopulate its damaged liver. iPSCs have their own problems: most iPSCs have multiple, large mutations. Putting mutant cells into someone is not exactly the best idea; not only would they be unlikely to work properly they'd also potentially form cancers. The second major problem is that iPSCs are also rejected by the host's immune system. This was quite unexpected, since iPSCs are theoretically genetically identical to their host. Changes to the cells that occur during their transformation into iPSCs seem to be recognized by the immune system, and the iPSCs are rejected. So the iPSC field now has two enormous hurdles to overcome; they must find cells that are both genetically stable and not rejected by the host's immune system. The two might have a similar solution but iPSCs are a long way from the clinic. The tail-becoming-liver experiment is still promising, but it used genetic modification with some nasty genes in order to perform its feat.  No tumours were found in the mice after 2 months, but the long-term effects remain to be determined.

Resident stem cells are perhaps the best prospect for stem cell therapies. Many of our organs have the capacity to regenerate themselves, at least partially. A person can have a big chunk of their liver removed and the resident stem cells will help it to grow back.  Bone marrow repopulates blood. Resident stem cells are specific to each organ but are already present in the body. The question is how to get them to grow when needed. Livers and blood regenerate themselves without needing to be stimulated, hearts and brains don't. Interestingly, a recent paper shows that resident stem cells in the mouse heart can grow and repopulate a damaged heart when the mouse is injected with a growth factor cocktail. The key to using resident stem cells will be finding the right cocktail for each organ. Some organs may not have stem cell populations that are inducible. It will take a lot of trial and error to find the right mix. The possibility of stimulating a population that's already in place is attractive since it circumvents the problems that arise when the cells are grown outside the body or genetically modified. Repopulating an organ from resident stem cells is a new idea and there will undoubtedly be problems along the way. Therapeutically it could only be used with partially damaged organs, since organs which are heavily damaged or removed completely wouldn't have the necessary stem cells. Some organs may not have resident stem cell populations, or those populations may not respond to growth cocktails. Neurons, for example, are particularly difficult to make. Things that work in mice don't always work in humans. And of course putting molecules into a human which stimulate growth could theoretically cause other inappropriate growth related diseases (ie cancers).

Few topics in biology have been as over-hyped as stem cells. They are a potentially powerful tool. Let's see what resident stem cell researchers come up with in the next few years.

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