I recently attended a fascinating lecture by Cambridge neuroscientist Robin Franklin on progenitor cells (“neural stem cells”) and their treatment potential in neurodegenerative diseases, such as multiple sclerosis (MS). The progressive form of MS, which follows from the relapsing-remitting version, stems from a decreasing ability of oligodendrocyte cells and their crucial myelin sheaths to be regenerated after they are destroyed through the course of the disease. Dr. Franklin’s lab studies cell remyelination, specifically focusing on oligodendrocyte precursor cells (OPCs), which are a form of progenitor that can evolve into oligodendrocytes to replace the damaged cells and sheaths. However, as an individual ages, these cells have a greater difficulty differentiating and do not regenerate as efficiently, which is most likely the cause in the transition to the progressive form of the disease. Dr. Franklin’s lab has used parabiosis to study the effects of aging on progenitor cell differentiation, the amazing science fiction-esque research method of fusing two mice together (in this case young and old), enabling them to share blood flow. From this research, Dr. Franklin has provided the most compelling evidence to date that decreases in crucial blood proteins as an individual ages are behind the increasing disability in remyelination and disease progression.
But let’s take a step back and do some defining, as I’ve just introduced a lot of jargon in that first section. Until only the last few decades, it was commonly thought that brain structure was relatively stable through adulthood, the window of neurogeneration and plasticity closing after adolescence. However this myth has been debunked, and there has been a revival in research on neural plasticity in adulthood and its potential treatment implications for individuals suffering from stroke, traumatic brain injury, and neurodegenerative diseases.
Multiple sclerosis (MS) is a neurodegenerative disease that consists of the breakdown of myelin sheaths, the protective coatings that surround cell axons and make up white matter tracts, enabling more efficient signal transmission between cells. This is in contrast to other neurodegenerative diseases, such as Huntington’s or Parkinson’s disease, which stem from the death of gray matter neurons themselves. These myelin sheaths originate from oligodendrocyte cells, bizarre looking neurons that consist of a cell body and up to 80 projections of giant wrap-around sheaths coming out of each arm. These sheaths encase and protect neighboring cell axons, however in MS both the sheaths and the oligodendrocyte cells become damaged, eventually breaking apart and dying.
Fortunately, the brain contains its own version of stem cells, early stage neurons called progenitor cells that have the potential to develop into a variety of different types of mature neurons. These progenitor cells are particularly adept at evolving into oligodendrocytes, and thus in the early stages of MS these lost cells can be replaced relatively easily. This depletion-repletion process explains the relapsing-remitting course of the early stages of MS. However, as the disease progresses it becomes increasingly difficult for these oligodendrocytes to regenerate, stemming from an increasing inefficiency in differentiation of the progenitor cells. This turn of events seems to define the later stage of progressive MS, though why this decline occurs has been unclear.
Enter Dr. Franklin and his team of researchers. Published recently in Cell Stem Cell, Dr. Franklin’s group used parabiosis to determine that the decreasing efficiency of cell regeneration was caused by an increase in age. Comparing heterochronic (young and old mice joined together) with isochronic (young-to-young or old-to-old) pairs, researchers damaged the myelin in the spinal cord of the older animals using a local toxin injection, and measured subsequent levels of both oligodendrocyte precursor cells (OPCs) and oligodendrocytes themselves. After 14 days, the levels of OPCs in the older damaged mice in the heterochronic pairs was significantly greater than those in the older isochronic animals, and at 21 days the levels of mature oligodendrocytes in old heterochronic animals were equivalent to those in young isochronic pairs. Both of these results were associated with an overall increase in myelination in the damaged heterochronic-old animals as compared to the isochronic-old pairs.
This improvement in regeneration seems to stem from an increase in differentiation of the already existing progenitors in the old mice, rather than a pilfering of these cells from their young counterparts. Instead, by joining together the vascular systems of the young and old animals, the older mice were able to benefit from increased levels of proteins and cells, such as macrophages, that signal the need for differentiation in the progenitors, enabling them to once again trigger the transformation process into full-fledged oligodendrocytes.
In his talk, Dr. Franklin was quick to point out that this was not a therapeutic study, but that it instead shows a pharmacological approach towards regeneration of oligodendrocytes for remyelination in MS may be promising going forward. These results suggest that it is not an influx of new progenitor cells that is needed in older individuals, but instead an enhancement of the signalling cells that make these transformations possible. This would of course be a far easier clinical undertaking than surgically fusing together young and old patients, and provides one of the first bits of evidence for treatment options in actually repairing the damage caused by neurodegenerative diseases.