Dr. Centeno at the Regenexx blog reports on a patient with arthritis of the hip who was deemed a poor candidate for a stem cell treatment, but went through with it anyway. The treatment failed and the patient ended up getting a hip replacement anyway.
Centeno’s entry on this case shows us that stem cells are not magic bullets. Sometimes they work and sometimes they do not. Furthermore they are not a one size fits all kind of treatment. Some patients are good candidates for stem cell treatments and some aren’t. Patients must be considered on a case-by-case basis.
Centeno has seen many successes with treating arthritic hips with his stem cell treatments. However, just as drugs and surgery are not magic bullets, neither are stem cells. Therefore, we should not expect them to be. They are powerful tools for healing, but they are not the equivalent of magic.
How do cells deal with junk? What would junk be to a cell? Sometimes proteins become unfolded or degraded, and such proteins are nonfunctional, which is to say that they become junk. Also, fats can become oxidized as can membrane lipids, and thus become junk. Sugars and degrade and become junk. Therefore, there are many ways that cells can acquire junk.
To deal with the junk, cells have a process known as autophagy, which is derived from two Greek words that mean “self” and “eat.” Autophagy is a vitally important process, because the breakdown of autophagy generates a lot of trouble for the cell. In fact, some diseases characterized by degeneration of the nervous system are characterized by a breakdown or overwhelming of autophagy.
As you might guess, autophagy is a highly regulated process. It consists of the formation of double- or multi-membrane vesicles called autophagosomes that enclose portions of the inside of the cells that are then delivered for degradation following fusion with lysosomes, which are the garbage disposals of the cell. If the cell revs up autophagy, then most of the proteins that are prone to clumping are quickly degraded. Such proteins are genetically linked to protein misfolding disorders (PMDs), and PMDs include diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Also, in cells, the accumulation of mutant proteins that tend to clump increases autophagy in cells and acts to detoxify the effects of these proteins.
These facts about autophagy suggest that it could be a good target for disease intervention. Also, many PMDs result from specific defects in particular steps of the autophagy process. Therefore, understanding this process is crucial for developing treatments to these diseases.
In the cell of people with Alzheimer’s disease (AD), there is a large accumulation of vesicles in the degenerating neurons. In a mouse model of AD, several studies have identified specific defects in the autophagy process. In a fascinating paper from the laboratory of Ralph Nixon, a protein called “presenilin-1” (PS1), regulates lysosomal function. In order for lysosomes to work, they must pumps hydrogen ions into their interiors. This acidifies the lysosome and activates the enzymes inside it. PS1, according to the Nixon paper targets the protein that pumps the hydrogen ions into the lysosome interior (v-ATPase, see Lee JH, et al., Cell. 2010 141(7):1146-58). PS1 is central to AD in humans because mutations in the gene that encodes PS1 lead to inherited forms of AD that tend to develop rather early in life. Autophagy requires PS1 and mutations in PS1 disrupt it. In the AD mouse, if genetic strategies are used to restore lysosomal function, the degeneration of the nervous system was halted prevented neuropathology and cognitive deficits of an AD mouse model (Yang DS, et al., Brain 2011, 134:258-277). Thus restoring lysosomal function in AD mice significantly decreases the accumulation of amyloid protein in the brain. This places autophagy impairment as an early feature in the pathology of AD.
Autophagy decreases as we age, and this is the main reason that our risk for developing PMDs increases as we age. Likewise, stimulating autophagy with drugs like rapamycin or resveratrol, or by means of caloric restriction, can cause anti-aging effects. In the mouse, inhibition of autophagy through genetic means causes their neurons to undergo spontaneous degeneration, not unlike what is observed in PMDs. The symptoms are also uncannily similar to other types of neurodegenerative diseases: death of neurons, motor dysfunction, and premature death (Komatsu M, et al., Nature 2006, 441:880-884 & Komatsu M, et al., Nature 2006, 441:880-884).
These data are the reason why introducing normal cells that can ingest and destroy aggregated proteins can possibly help patients with PMDs. Thus even though stem cells may not be able to rewire the damaged brain of an AD patient, by designing stem cells that can clean up the brain and improve the autophagy of the brain, we might be able to improve the clinical outcomes of AD patients and other patients with PMDs.