Abnormal Lipid Metabolism Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease

The brain is deeply dependent on lipid (fatty molecule) metabolism for proper development and function. Could abnormal lipid metabolism affect the brain’s stem cell population? Oh yes.

Karl J.L. Fernandez and his coworkers from the Research Center of the University of Montreal Hospital in Montreal, Canada and other collaborators has shown that neural stem cell populations in the brain can be compromised by abnormal lipid metabolism and that such abnormalities are characteristic of Alzheimer’s disease.

3xTg-AD mice form plaques in their brains that are similar to those in the brains of Alzheimer’s disease patients. Fernandez and his colleagues discovered that 3xTg-AD mice accumulate lipids within ependymal cells, which line the ventricles of the brain and serve as the main support cell of the forebrain Neural Stem Cells (NSCs). Interestingly, brains from Alzheimer’s disease patients, when examined after death also showed the accumulation of lipids within the same cell population.


When these lipids were examined further, it was clear that they were oleic acid-enriched fats (oleic acid is found in olive oil). In fact, injecting oleic acid into this area of the brain could recapitulate this pathology. When Fernandez and others inhibited oleic acid synthesis, they were able to fix the stem cell issues in the 3xTg-AD mice.

This fascinating study shows that the pathology in Alzheimer’s disease might be caused by perturbation of fatty acid metabolism in the stem cell niche that suppresses the regenerative functions of NSCs. Preventing accumulation of these fats in the cells surrounding the NSC population can potentially fix the stem cell abnormalities in patients with Alzheimer’s disease.

This study was published in the journal Cell Stem Cell.

Non-Randomized Stem Cell Study for Knee Osteoarthritis Yields Positive Results

A peer-reviewed study that was neither placebo-controlled nor randomized, but did examine 840 patients, has shown that the use of a patient’s own bone marrow stem cells are both safe and effective.

Christopher Centeno and his colleagues, who pioneered the Regenexx protocol, use live-imaging to guide the application of stem cells to the site in need of healing. Centeno and others have established several clinics around the United States that utilize the Regenexx system, and the data published in this paper came from these clinics, in addition to Chris Centeno’s own clinic in the Denver, Colorado area.

In this study, patients self-rated their lower extremity functional using a lower extremity functional scale (LEFS), and their knee pain by using a numerical pain scale (NPS). Patients had bone marrow extracted through a bone marrow aspiration. These bone marrow cells were isolated and concentrated, and then prepared for reinvention. In addition, platelet rich plasma (PRP) and platelet lysate (PL) were prepared from the patient’s own blood and these, with the bone marrow cells, were injected into the knee under guided imaging. The frequency and types of adverse events (AE) were also recorded by the physicians.

Some of these patients had fat overlaid on their knee lesions in addition to their bone marrow cells. Of the 840 procedures that were performed, 616 had treatment without additional fat, and 224 had treatment with the fat graft. This was to determine if the use of fat, with its resident stem cell population, augmented healing of the arthritic knee.

When the LEFS scores before and after the Regenexx procedure were compared, an increase of 7.9 and 9.8 in the two groups (out of 80) was observed. The mean NPS score decreased from 4 to 2.6 and from 4.3 to 3 in the two groups. AE rates were 6% and 8.9% in the two groups. An examination of these data showed that pre- and posttreatment improvements were statistically significant. However, the differences between the fat- and fat+ groups were statistically insignificant.

The patients in this study suffered from osteoarthritis. Consequently, they were experiencing significant knee pain and many were candidates for a knee replacement. Many of these patients were able to avoid knee replacement by undergoing the Regenexx procedure.

The study concluded that there was no advantage of adding fat to the joint over the bone marrow cells. Safety in both groups (with and without fat) was excellent compared to knee replacement.

This study used data from patients who were part of the Regenexx registry. Therefore, this study was not a randomized, controlled study, like the kind that are used to test drugs. Randomized controlled trials are being conducted by Centeno and his colleagues at the various Regenexx centers. A knee osteoarthritis study is being studied in Chicago, another study regarding shoulder rotator cuff tears, and a third study examining ACL tears are in progress.

Stem Cell-like Megakaryocyte Progenitors Replenish Platelets After Inflammatory Episodes

A paper that appeared in the journal Cell Stem Cell from the laboratory of Marieke A.G. Esters, from the Heidelberg Institute for Stem Cell Technology and Experimental Medicine in Heidelberg, Germany has answered a long-standing question about how our bodies regenerate platelets using so many of them.

When we suffer damage to our bodies from surgery, accidents, infections, or other physical insults, we tend to use a lot of platelets. Platelets are small cells in the blood that help the blood clot once we cut ourselves. Platelets, however, take some time to form. How then do we rapidly regenerate the platelet pool during such stressful conditions?

Esters and her team have shown that the bone marrow contains stem-like cell called a “single-lineage megakaryocyte-committed progenitor” or SL-MkPs. Platelets bud from a large cell called a “megakaryocyte,” and megakaryocytes form from the hematopoietic stem cells that reside in the bone marrow. Hematopoietic stem cells make all the blood cell that course through our blood vessels and continue to replace those cells throughout our lifetime. Hematopoietic stem cells personify what it means to be a multipotent stem cell.

Haas et al, graphical abstract 5.5x5.5

This newly-identified stem cell population, the SL-MkP actually shares many features with multipotent hematopoietic stem cells and provides a stem cell population that is lineage-restricted (that means they can only form one type of cell) for emergency purposes.

Normally, SL-MkPs are maintained in an inactive, almost sleep-like state. In this state, SL-MkPs do not contribute very much to making platelets in the blood. There is some gene expression in this sleepy state, but protein synthesis is turned way down.

In response to acute inflammation, SL-MkPs wake up and become activated. Upon activation, these cells ramp up protein synthesis and mature into full-blown SL-MkPs that efficiently replenishment of platelets that are lost during high levels of inflammation. Thus, there is an emergency system that accommodates platelet depletion during acute inflammation and replenishes the platelet pool.

Activation of Dormant Viruses May Cause ALS

Inactive viruses that litter the human genome may become reactivated and contribute to the development of motor neuron disease, according to new research published today in the journal Science Translational Medicine.

Human endogenous retroviruses (HERVs) are the flotsam and jetsam of ancient viruses that integrated into our chromosomes long ago as the results of retrovirus infections that occurred over several million years of our history.  These HERV sequences account for about 8% of human DNA and the vast majority of them have acquired multiple genetic mutations that made rendered them innocuous.  Therefore, HERVs are sometimes referred to as “junk” DNA, although some of these sequences have been shown to have function (for example, see Dupressoir A, Lavialle C, Heidmann T. Placenta. 2012 Sep;33(9):663-7).

In 2011, Avindra Nath, the intramural clinical director of the National Institute of Neurological Disorders and Stroke, and his colleagues reported that proteins synthesized by one such HERV known as HERV-K are found in very high concentrations in the brains of patients who died of amyotrophic lateral sclerosis (ALS), which is a progressive and fatal neurodegenerative disease that destroys those motor neurons that control speech, movement, swallowing and breathing, which leads to death between three to five years after the symptoms first appear.

In their new study, Nath’s research group investigated the toxicity of viral proteins to nerve cells. They examined samples of nervous tissue from 11 patients who had died of ALS, 10 Alzheimer’s patients, and 16 people who showed no signs of neurological disease as controls.  They used RNA sequencing to confirm that transcripts of three HERV-K genes are present in tissue samples from the ALS patients but not in those from the Alzheimer’s patients or control patients.  In their next set of experiments, Nath and his coworkers showed that the proteins encoded by these viral genes localized to motor neurons in the brains and front halves of the spinal cords of ALS patients.  This is significant, since the ventral or font portions of the spinal cord contains the cell bodies of motor neurons that send their axonal fibers to the body’s skeletal muscles where they synapse with those muscles.  Thus the presence of the viral proteins strongly correlates with the tendency of these cells to die.

To definitively test the toxicity of these viral proteins to neurons, Nath and others transfected either the entire viral genome, or just the viral env gene, which encodes the virus’s coat protein, into cultured human neurons.  Once integrated into the genomes of the cultured cells, the viral genes were fully activated and used the cell’s molecular machinery to synthesize their respective proteins.  Expression of these viral genes killed off significant numbers of cells and caused them to retract their neural fibers.  Furthermore expression of only the env gene in these cultured neurons was sufficient to kill them.

To test their hypothesis in a living animal, Nath and others generated a strain of genetically engineered mice whose neurons express high levels of the HERV-K env gene.  Behavioral tests showed that these HERV-K env+ animals developed motor function abnormalities; they had difficulty walking and balancing compared to healthy mice.  These symptoms progressed rapidly between 3 and 6 months of age, and half of the animals had died before or shortly after reaching 10 months of age.

Closer examination revealed that neurons in the motor cortex had degenerated.  They also showed a decrease in the length, branching and complexity of dendrites, and a reduction in the number of dendritic spines (small, finger-like extensions that receive chemical signals from other cells).

All of these data strongly suggest that reactivation of dormant HERV-K contributes to neurodegeneration in the brain and spinal cord.  The absence of this virus in the brains of Alzheimer’s patients supports the conclusion that reactivation of it causes degeneration, rather than being a consequence of it, and further suggests that it is specific to ALS.

ALS is associated with genetic mutations in more than 50 different genes.  However, as is the case for Alzheimer’s, these inherited forms of the disease, which account for just 10-15% of cases. But this study only examined patients with sporadic, or non-inherited, ALS, the cause of which have been much harder to pin down.

Further genetic analyses may identify DNA sequence variations, in the HERV-K genes themselves, and others that interact with them, which might make the virus more prone to reactivation.  More work will need to be done to determine exactly how the reactivated virus genes contribute to the disease.

Meanwhile, Nath and his colleagues are collaborating with researchers at Johns Hopkins University to determine if anti-retroviral drugs might alleviate disease symptoms in subsets of ALS patients.

See Li, W., et al. (2015). Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Trans. Med., 7: 307ra153.

Stem-Cell Dental Implants Grow New Teeth in Your Mouth

Dr. Jeremy Mao is the Edward V. Zegarelli Professor of Dental Medicine at Columbia University Medical Center. Mao and his colleagues have published a novel technology that includes a growth factor-infused, three-dimensional scaffold that has the potential to regenerate an anatomically correct tooth in the mouth just nine weeks after implantation. By this procedure, which was developed in the university’s Tissue Engineering and Regenerative Medicine Laboratory, Mao can direct the body’s own stem cells to migrate to the scaffold and infiltrate it. Once these stem cells have colonized the scaffold, they will produce a tooth that can grow in the socket and merge with the surrounding tissue and integrate into it.

Tooth scaffold that is completely composed of natural materials.
Tooth scaffold that is completely composed of natural materials.

Mao’s technique not only eliminates the need to grow teeth in a culture, but it can regenerate anatomically correct teeth by using the body’s own resources. If you factor in the faster recovery time and the comparatively natural process of regrowth (as opposed to implantation), you have a massively appealing dental treatment.

Columbia University has already filed patent applications in regard to this technology. They are also seeking associates to aid in its commercialization. Mao is also considering the best approach for applying his technique to cost-effective clinical therapies.