MS is a neurodegenerative disease characterized by inflammation and scar-like lesions throughout the central nervous system (CNS). There is no cure and no treatment eases the severe forms of MS. But previous studies on animals have shown that transplantation of mesenchymal stem cells (MSCs) holds promise as a therapy for all forms of MS (see Bai L, et al., Glia 2009 Aug 15;57(11):1192-203). The MSCs migrate to areas of damage, release trophic (cell growth) factors and exert protective effects on nerves and regulatory effects to inhibit T cell proliferation.
Several clinical trials examining the ability of fat-derived MSCs to treat MS patients have been conducted. Unfortunately, most of these studies are rather small and the results are all over the place. One study treated ten patients with MSCs injected intrathecally (just under the meninges that cover the brain and spinal cord) and the results were mixed; 6/10 improved, 3 stayed the same and one deteriorated. Another study treated ten patients with intravenous fat-derived MSCs and the patients showed symptomatic improvement, but when MRIs of the brain were examined, no improvements could be documented. A third study treated 15 people with intrathecal injections and IV administrations of MSCs, and some stabilized. A fourth study only examined 3 patients treated with a mixture of their own fat-derived MSCs and fat-derived MSCs from another person. In all three cases, their MRIs and symptoms improved. A fifth study used umbilical cord MSCs administered intravenously and the patient showed substantial improvement (for review see Tyndall, Pediatric Research 71(4):433-438).
These results are somewhat encouraging, but also somewhat underwhelming and clinical trials go. Why did some work and other not work as well? In order to understand why, researchers must understand the biologic changes and therapeutic effects of older donor stem cells. A new study appearing in the journal STEM CELLS Translational Medicine is the first to demonstrate that adipose-derived MSCs donated by older people are less effective than cells from their younger counterparts.
Fortunately, all the available MS-related clinical trials have confirmed the safety of autologous MSC therapy. As to the efficacy of these cells, however, it is unclear if MSCs derived from older donors have the same therapeutic potential as those from younger ones.
“Aging is known to have a negative impact on the regenerative capacity of most tissues, and human MSCs are susceptible to biologic aging including changes in differentiation potential, proliferation ability and gene expression. These age-related differences may affect the ability of older donor cells to migrate extensively, provide trophic support, persist long-term and promote repair mechanisms,” said Bruce Bunnell, Ph.D., of Tulane University’s Center for Stem Cell Research and Regenerative Medicine. He served as lead author of the study, conducted by a team composed of his colleagues at Tulane.
In their study, Bunnell and his colleagues induced an MS-like disease in laboratory mice called chronic experimental autoimmune encephalomyelitis (EAE). Then they treated them before disease onset with human adipose-derived MSCs derived from younger (less than 35 years) or older (over age 60) donors. The results corroborated previous studies that suggested that older donors are less effective than their younger counterparts.
“We found that, in vitro, the stem cells from the older donors failed to ameliorate the neurodegeneration associated with EAE. Mice treated with older donor cells had increased inflammation of the central nervous system, demyelination leading to an impairment in movement, cognition and other functions dependent on nerves, and a proliferation of splenocytes [white blood cells in the spleen], compared to the mice receiving cells from younger donors,” Dr. Bunnell noted.
In fact, the proliferation of T cells (immune cells that attack the myelin sheath in MS patients) in these mice indicated that older MSCs might actually stimulate the proliferation of the T cells, while younger stem cells inhibit T cell proliferation. T cells are a type of white blood cell in the body’s immune system that help fight off disease and harmful substances. When they attack our own tissues, they can cause diseases like MS.
As such, Dr. Bunnell said, “A decrease in T cell proliferation would result in a decreased number of T cells available to attack the CNS in the mice, which directly supports the results showing that the CNS damage and inflammation is less severe in the young MSC-treated mice than in the old MSC-treated mice.”
“This study in an animal model of MS is the first to demonstrate that fat-derived stem cells from older human donors have less therapeutic effectiveness than cells from young donors,” said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. “The results point to a potential need to evaluate cell therapy protocols for late-onset multiple sclerosis patients.”