BGRF Funds A Major New Study Into Haematopoietic Stem Cell Transplantation And Cancer

The BGRF, a UK charity is funding a major study investigating the therapeutic potential of transplanting Haematopoietic stem cells to evaluate how they can affect the aging process specifically in relation to the increasing risk of cancer with age.

Feb 25, 2011 – The Biogerontology Research Foundation (BGRF) is a UK registered charity which is committed to the support of aging research in order to address the challenges of a rapidly aging population and to reduce the impact of disease on future generations. BGRF are in the second year of funding an ambitious project in which researchers from the Max Planck Partner Group Program on Stem Cell and Aging Research in Beijing and Ulm (Germany) are investigating the therapeutic potential of transplanting Haematopoietic (blood) stem cells into mice. This exciting project intends to evaluate the principle that stem cell transplantation could be useful in combating the aging process specifically in relation to the increasing risk of cancer with age, given an improved stem cell environment.

Cancer is probably going to be the hardest aspect of aging to defeat, because it has natural selection at its disposal. Some of the most promising approaches to combating cancer try to fight fire with fire, i.e. to use natural selection against it, by optimising the immune system’s anti-cancer potential, but even this approach has yet to show decisive results. BGRF are funding a project that seeks to put in place one key part of a radically new therapy, which tackles the evolutionary prowess of cancer head-on.

The approach consists of two parts: one involving gene therapy, the other involving stem cell therapy. The gene therapy part involve deleting the genes necessary for the elongation of telomeres (the ends of our chromosomes). Cancers cannot grow large enough to be fatal for humans without expressing such genes, so even the high mutation rate in a cancer cannot save it if these genes are missing from its DNA. However, in order to be sure that we delete these genes from every cell that could form a cancer, we have to delete them from every cell in the body that is capable of dividing – including cells that need to divide hundreds of times during life in order to maintain our bodies. Luckily, though, there are only three or four such cell types, namely the stem cells of the blood, skin, gut and possibly lung – and in each case it seems likely to be sufficient to replenish these stem cells every decade or so with new ones that initially have long telomeres. The project being funded by BGRF is investigating this stem cell replenishment process in mice, in respect of the blood.

Mice are the model organism of choice in most early-stage development of pioneering medicine, because they are easy to manipulate genetically, are relatively short-lived, and are anatomically quite similar to humans. That is true here too, though in this case the necessary manipulation is quite elaborate. First, the researchers need to use mice in whom the most important telomere-elongating genes have been removed really thoroughly, not by gene therapy but by a procedure called “knockout”, which is much simpler but cannot be done in animals that are already alive. Then, they need to alter their genes in a second way, which partially protects their gut stem cells but not their blood stem cells from the effects of telomere shortening, so that the first thing that goes seriously wrong in the mice is their blood. Finally, they have to prepare blood stem cells (“HSCs”) for transplant into these mice that can be distinguished from the recipient’s own blood by the presence of a genetic marker. BGRF have been fortunate to secure the enthusiastic interest of the world leader in this area, Prof. Lenhard Rudolph of the University of Ulm, and his long-time collaborator Dr. Zhenyu Ju of the University of Beijing. These researchers were responsible for much of the groundwork that makes this project feasible, and no one is so well placed to perform it. In previous work (prior to BGRF involvement), these researchers found that transplantation of wild type HSCs with long telomere reserves could not rescue the premature aging of late-generation telomerase-deficient mice, due to age–dependent cell-extrinsic alterations impairing stem cell engraftment and function. The current project is designed to further explore the potential therapeutic value of stem cell transplantation in age-related telomere-dependent tissue degeneration under the condition of a rejuvenated cell-extrinsic environment.

The group’s preliminary data showed that Exo-1 deletion rescued the age-dependent environmental defects in telomere dysfunctional mice, but did not improve the HSC-intrinsic defects, as tested by a competitive re-population assay. These double-knockout (Exo-1 and telomerase) mice were transplanted with wild type HSCs at various ages, and will be followed up until death. If the experiment succeeds, the results will provide proof of the principle that stem cell transplantation could be useful in combating the aging process specifically in relation to the increasing risk of cancer with age – given an improved stem cell environment.

The project has now been running for a year, and all the above tools and reagents have been successfully developed. During the remainder of the project, we will be able to use these tools to determine whether mice that are becoming anaemic due to the telomere-mediated failure of their blood stem cells can be revived by the introduction of new stem cells that are also unable to extend their telomeres but initially have long telomeres. In June 2011 Dr Zhenyu Ju will be presenting his findings on this project at the American Aging Association meeting in Raleigh, North Carolina, between the 3rd and 6th of June 2011.

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