At the recent “World Stem Cell Summit” meeting in Pasadena, CA, I chaired a session on the topic of utilizing endogenous stem cells (SCs) to treat disease. Endogenous refers to the idea of making use of the body’s own, resident SCs. These cells are found in all tissues of the developing as well as the adult organism (gut, heart, brain, blood, retina etc). This approach is totally different from the more widely used and famous one of transplanting SCs produced from an embryo, or another adult donor, or one’s own (modified) SCs, into the body of patient to treat their disease. The most widely used and famous example of SC grafting involves bone marrow transplantation, which is most commonly used in the case of cancers of the circulatory system. Although transplanting SCs holds great promise for a wide variety of conditions, there are a number of issues with this approach. In addition to the ethical controversies surrounding the use of human embryonic SCs, there is the problem of growing up enough cells in a highly purified form, and converting them to the the appropriate cell type before transplantation. Then there can the problem of suppressing the immune system of the recipient patient, which may try to reject the grafted cells. Another issue is making sure that the grafted cells do not continue to divide and form a tumor. While researchers around the world are making steady progress in confronting and overcoming these problems, some hurdles still remain.
Mobilizing the body’s own SCs avoids all of these issues. Two of the speakers at the Summit meeting used this approach in treating mouse models of diseases of the brain. The adult brain has several types of SCs that slowly but continuously give rise to new neurons and glial cells throughout life. Moreover, there is evidence that in several human neurodegenerative diseases SCs are activated to produce more cells near the injury or disease site. Unfortunately, this response to disease is not robust enough to prevent the disease. Therefore, it is of interest to see if this normal but insufficient response can be stimulated to do a better job of replacing dying cells. Abdel Benraiss from Steve Goldman’s laboratory at the University of Rochester discussed his work on Huntington’s disease (HD)(J Clin Invest; Gene Therapy). HD is a tragic genetic disease in which neurons die in specific parts of the brain, leading to spastic, uncontrolled movements and eventual death. There is no adequate treatment for this disease at present. However, Goldman’s group has shown in a mouse model of HD that the dying neurons can be very effectively replaced when the endogenous neural SCs in the adult brain are appropriately stimulated. The method involves gene therapy – injecting the brain with genes that stimulate and guide the development of SCs into the type of neurons that need to be replaced. This treatment leads to amelioration of the movement abnormalities of the disease and also significantly prolongs the lifespan of the HD mice.
A similar gene therapy approach, but in a mouse model of multiple sclerosis (MS), was presented by Ben Deverman, a senior postdoctoral researcher in our group (php lab). In this MS model, neurons in the brain are demyelinated by a chemical given in the drinking water. Ben then injected the brain with a gene coding for the cytokine, LIF, which we and others had shown goes up in many types of injuries and diseases. (Cytokines are discussed extensively in my book) Thus, LIF is a natural responder to injury and inflammation such as that seen in MS. In the mouse MS model, when LIF is increased by this therapy, it stimulates the replacement of the lost oligodendrocytes, the cells that myelinate nerves. The result is that there is considerable remyelination of denuded neurons. That LIF is a good candidate for further work on demyelinating diseases is also shown in a new paper by Cao et al. (see commentary by Su Metcalf). They found that LIF suppresses rogue TH17 cells that can cause autoimmune inflammation.
Although these examples are from mouse models rather human clinical trials, they provide proof of concept that gene therapy can be used to successfully mobilize the adult brain’s endogenous SCs and progenitor cells for use in repairing diverse diseases of the nervous system.