Increased cholesterol synthesis drives neurotoxicity
in patient stem cell-derived model of multiple sclerosis
R. B. Ionescu, A. M. Nicaise, J. A. Reisz, E. C. Williams, P. Prasad, C. M. Willis, et al.
Cell Stem Cell; Volume 31, Issue 11, 7 November 2024, Pages 1574-1590.e11
Introduction:
Cholesterol is a major component of myelin, the fatty substance produced by brain cells called oligodendrocytes. Myelin serves as an insulator around nerve cell fibers (axons) and is a major target of the immune attack on the brain. Loss of myelin is associated with nerve cell death and tissue scarring. Immature oligodendrocytes are numerous at sites of myelin loss, but the cells appear blocked from maturing and are unable to regenerate new myelin (remyelination). Reasons for this block are not known.
Several groups of scientists have studied myelin metabolism, specifically cholesterol metabolism. Results showed an association between levels of certain cholesterols and the clinical status of persons with MS.
Based on the results of these studies clinical trials of drugs such as statins were instituted to determine if modifying cholesterol metabolism was of benefit in controlling their MS. Results were mixed. Some trials showed benefits in relapsing forms of multiple sclerosis but no benefit in progressive multiple sclerosis. Some showed a worsening of disease .
In this context, the recent paper by Ionescu and colleagues, noted above, provides important data that could result in a new therapeutic approach in the treatment of MS.
Key Points:
1. The central nervous systems of persons with MS show signs of premature aging or senescence. Signs of premature senescence are especially prominent in chronic active lesions of persons with progressive disease. Importantly, such changes are present even at onset of the disease, gradually increasing over time.
2. With aging (senescence), cells change, either acquiring new traits or losing previous ones. Changes in the metabolism of fats or lipids are a characteristic of senescent cells.
3. Senescent cells secrete a cocktail of proteins associated with inflammation called senescence-associated secretory phenotype (SASP). This cocktail includes a variety of inflammatory cytokines as well as agents toxic to brain cells.
4. Ionescu and colleagues took skin cells from 3 persons with progressive MS and 4 normal individuals. They reprogrammed the cells in tissue culture to become neural stem cells, cells able to differentiate into other cells of the central nervous system.
5. The researchers noted that neural stem cells from persons with progressive MS showed signs of senescence that was not present in normal individuals’ cells. Senescence was manifested by signs of increased inflammation, hypermetabolism presenting as an increased utilization of glucose, increased activation of senescence-associated genes, an increased secretion of senescence-associated proteins (SASP), and increased production of fatty acids and cholesterol.
6. When culture medium from cells from persons with progressive MS were added to nerve cells in tissue culture, the nerve cells died. This did not occur with culture medium from normal individuals’ cells.
7. These observations indicated that senescent cells in MS lesions produced a SASP that contained a nerve-cell killing toxin in association with increased production of fatty acids and cholesterol, resulting in chronic inflammation and tissue destruction in the absence of immune cells.
8. The investigators then reduced cholesterol production by treating the neural stem cells with the statin simvastatin. While most of the components of SASP were not affected, levels of the nerve-cell toxin were reduced to normal.
9. These observations, in addition to those from other laboratories, indicated an intrinsic, “hypermetabolic rewiring” of cholesterol metabolism in neural stem cells from persons with progressive MS, leading to the production of toxins that can kill nerve cells. Other researchers had also shown that SASP produced by cells from persons with progressive MS prevented oligodendrocytes from forming new myelin.
10. Three clinical trials to date studied the effects of simvastatin in persons with progressive MS, and optic neuritis. No benefits were not noted regarding acute central nervous system changes (relapses or MRI lesions), changes usually resulting from immune system effects. Benefits were noted in changes related to non-immune mediated degeneration, specifically a significant decrease in the rate of brain atrophy.
11. It’s not clear why trials of statins did not provide greater benefit, but in view of the findings of Ionescu et al. what is now needed are drugs that can easily penetrate the central nervous system and modify cholesterol metabolism such that SASP-related toxicity is reduced. Once found and tested, such treatment could modify tissue damage in ways not addressed by current therapies, involving mechanisms of non-immune mediated degeneration that appears to be present from onset of the disease.
Discussion:
Current disease-modifying therapies successfully treat the acute inflammation present in relapsing forms of MS. None of the currently available disease-modifying therapies are able to change the course of progressive MS.
A major component of tissue loss in progressive MS is “degenerative.” This usually means there is an abnormality of central nervous system tissue such that the tissue cannot sustain itself. Most importantly, this degenerative process occurs without the participation of the peripheral immune system. While degeneration is most prominent in the latter phases of MS, changes of degeneration are seen even at disease onset. The result is progressive disability early in the illness in the absence of relapses.
One possible explanation for degenerative processes in MS is that the central nervous systems of persons with MS age more rapidly than expected with metabolic changes associated with more rapid aging or senescence.
Biologically senescent cells are found in lesions of chronic, “degenerative” inflammation. These cells are metabolically active, secreting a mixture of substances called senescence-associated proteins or SASP. SASP consists of pro-inflammatory cytokines, growth factors, cytotoxic mediators, metalloproteinases and reactive oxygen species (ROS). These secretions affect neighboring cells, converting them to a senescent state, further increasing tissue damage.
Associated with premature aging in persons with MS is a change in fat or lipid metabolism, in particular cholesterol metabolism. Changes in levels of cholesterols correlate with changes in the clinical state and in MRI measures. The paper by Ionescu and colleagues offers insight into a connection between altered cholesterol metabolism, senescence, and tissue degeneration.
By reprogramming skin cells from persons with progressive MS and controls to form neural stem cells the scientists showed that cells derived from the outer layer of skin cells, the ectoderm, were senescent in persons with progressive MS, secreted SASP, were hyper-metabolic in their utilization of glucose and had increased production of cholesterol. Similar changes were previously noted by other investigators, with one study implicating an effect of senescence on remyelination,
Ionescu and collaborators showed that SASP from neural stem cells from persons with progressive MS was toxic to nerve cells (neurons) in tissue culture. When these cells were exposed to the statin simvastatin the levels of the SASP toxin was reduced to normal, with an increase in several neuroprotective substances. There are important implications of the Ionescu and colleagues findings. Some are positive. Some are negative.
On the positive side, and potentially most importantly, is that senescent cells in MS brains contribute to smoldering, chronic inflammation and tissue destruction in the absence of any immune cells, and that senescent brain cells can have their tissue toxicity modified by reducing production of lipids, in particular cholesterol. To date, the data on use of cholesterol-reducing statins as a treatment for progressive MS is mixed, with some trials suggesting benefit and others suggesting a worsening of disease. The complexity is further increased by observations that statins can have opposing effects, based on drug concentrations, with some dosages ameliorating senescent changes and other dosages increasing senescent changes.
On the negative side, these data throw into question the value of autologous bone marrow transplants as treatment for MS. If stem cells in progressive MS are already “pre-wired” to have a senescent format, as suggested by Ionescu et al.’s and other’s work, bone marrow stem cell transplantation may prevent recurrent acute inflammation but will not prevent chronic disease progression, since smoldering disease may not be affected. Data supporting this conjecture have been reported.
The challenge to altering senescence characteristics and achieving a major therapeutic breakthrough is to find a cholesterol-modifying drug that penetrates the central nervous system, has an acceptable side effect profile, is easily administered, is not excessively costly and is able to modify secretion of SASP. Adding to this challenge is defining a therapeutic effect in a slowly progressive, chronic illness. This will take a large number of participants followed for longer than the currently usual two-year length of study. Costs for such a trial will be high and probably involve multiple centers. As a result, finding a funding source will prove a challenge. In any case, Ionescu and coinvestigators have presented the MS community with data that could evolve into the development of a major therapy for persons with progressive MS, something urgently needed and currently lacking. Hopefully, the challenge will be met.
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