Mechanism that Prevents Stem Cell Aging


A research group at the University of Valencia, Spain, led by Isabel Fariñas Gómez, at the Molecular Neurobiology Unit, has discovered a mechanism that maintains stem cell populations in the brain and prevents these stem cells from overproliferating early in life and burning out.

Gómez’s group has discovered that the product of the CDKn1a/p21 gene is essential for maintaining brain stem cells.  By keeping these stem cells active and functional, the brain dynamically changes as it learns and remembers, and maintains its good state of health.  In the absence of p21, brain stem cell populations deplete and this prevents the formation of new neurons toward the end of life.

Stem cells require p21 to replicate themselves in a controlled fashion.  In other cell types, p21 acts as a “tumor suppressor” gene.  Tumor suppressor genes encode proteins that tend to put the brakes on cell proliferation.  Loss-of-function mutations in tumor suppressor genes causes uncontrolled group and predisposes that cell and its descendants to become cancer cells.

p21 function

However, in neural stem cells, p21 functions differently.  Depletion of p21 from neural stem cells causes their depletion rather than their overgrowth.  In short, an absence of p21 causes these cells to age.

This research, conducted in collaboration with Anxo Vidal from the University of Santiago de Compostela, shows that p21 in neural stem cells restrains the production of molecules that induce the depletion of these this stem cell population.  Thus p21 restricts aging.  According to Fariñas Gómez, “The research allows us to understand better how stem cells get lost in our brains as we age, and opens the possibility to try to alleviate this deterioration.”

Stomach Cells Naturally Revert to Stem Cells


George Washington University scientists from St. Louis, Missouri have found that the stomach naturally produces more stem cells than previously realized. These stem cells probably repair stomach damage from infections, the foods we eat, and the constant tissue insults from stomach acid.

The reversion of adult cells to a stem cell fate is one of the goals of stem cell research. Shinya Yamanaka’s research group at the Center for iPS Cell Research and Application and the Institute for Frontier Medical Sciences at Kyoto University won the Nobel Prize in 2012 for his work on reprogramming adult cells into embryonic-like stem cells, otherwise known as induced pluripotent stem cells (iPSCs) that was initially published in 2006.

A collaborative research effort between scientists from Washington University School of Medicine in St. Louis and Utrecht Medical Center in the Netherlands have shown that this reversion from adult cells to stem cells occurs naturally in the stomach on a regular basis.

Jason Mills, associate professor of medicine at Washington University, said, “We already knew that these cells, which are called chief cells, can change back into stem cells to make temporary repairs in significant stomach injuries in significant stomach injuries, such as a cut to damage from infection. The fact that they’re making this transition more often, even in the absence of noticeable injuries, suggests that it may be easier than we realized to make some types of mature, specialized adult cells revert to stem cells.”

Chief cells normally produce a protein called pepsinogen. In the presence of stomach acid, pepsinogen activates itself and once active, the new protein product, pepsin, degrades proteins. Pepsin in an enzyme that is most active in the acidic environment of the stomach. Another enzyme released by chief cells is chymosin, which is also known as rennet. Chymosin curdles the proteins in milk and makes them easier to degrade.

PARIETAL AND CHIEF Cells

Mills and his groups are in the process of studying the transformation of chief cells into stem cells, for injury repair. Mills would also like to investigate the possibility that the potential for growth unleashed by this change may contribute to stomach cancers.

Mills and his collaborator Hans Clevers from the Netherlands have identified stomach stem cell marker proteins that show that chief cells become stem cells even in the absence of serious injury. In the case of serious injury, either in cell culture of in animal models, more chief cells become stem cells, making it possible to repair the damage in the stomach.

Faulty Stem Cell Regulation Contributes to Down Syndrome Deficits


People who have three copies of chromosome 21 have a genetic condition known as Down Syndrome (DS). In particular, patients who have an extra copy of a small portion of chromosome 21 (q22.13–q22.2) known as the Down Syndrome Critical Region or DSCR have the symptoms of DS. The DSCR contains at least 30 genes or so and some of them tightly correlate to the pathology of DS. For example, the APP (amyloid protein precursor) gene accounts for the accumulation of amyloid protein in the brains of DS patients. DS patients develop Alzheimer disease-like pathology by the fourth decade of life, and the APP protein is overexpressed in the adult Down syndrome brain. Another gene found in the DSCR called DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) encodes a member of the dual-specificity tyrosine phosphorylation-regulated kinase family and this protein participates in various cellular processes. Overproduction of DYRK1A seems to cause the abnormal brain development observed in DS babies.

Another gene found in the DSCR is called USP16 and this gene encodes a protein that removes small peptides called ubiquitin from other proteins. Ubiquitin attachment marks a protein for degradation, but it can also mark a protein to do a specific job. USP16 removes ubiquitin an either stops the protein from acting or prevents the proteins from being degraded. Overexpression of UPS16 occurs in DS patients, and too much UPS16 protein affects stem cell function.

Michael Clarke, professor of cancer biology at the Stanford University School of Medicine, said, “There appear to be defects in the stem cells in all the tissues we tested, including the brain.” Clarke continued, “We believe USP16 overexpression is a major contributor to the neurological deficits seen in Down Syndrome.” Clarke’s laboratory conducted their experiments in mouse and human cells.

Additional work by Clarke and his colleagues showed that downregulation of USP16 partially rescues the stem cell proliferation defects found in DS patients.

Clarke’s study suggests that drugs that reduce the activity of USP16 could reduce the some of the most profound deficits in DS patients.

This paper also details some of the pathological mechanisms of DS. DS patients age faster and exhibit early Alzheimer’s disease. The reason for this seems to rely on the overexpression of UPS16, which accelerates the rate at which stem cells are used during early development. This accelerated rate of stem cell use burns out and exhausts the stem cell reserves and, consequently, the brains age faster and are susceptible to the early onset of neurodegenerative diseases.

After examining laboratory mice that had a rodent form of DS, Clarke and his coworkers turned their attention to USP16 overexpression in human cells. Clarke collaborated with a Stanford University neurosurgeon named Samuel Cheshier and their study showed that skin cells from normal volunteers grew much more slowly when the Usp16 gene was overexpressed. Furthermore, neural stem cells, which normally clump into little balls of cells called neurospheres, no longer formed these structures when Usp16 was overexpressed in them.

a, Proliferation analysis, as well as SA-βgal and p16Ink4a staining, of three control and four Down’s syndrome (DS) human fibroblast cultures show growth impairment and senescence of Down’s syndrome cells. b, c, Lentiviral-induced overexpression of USP16 decreases the proliferation of two different control fibroblast lines (b), whereas downregulation of USP16 in Down’s syndrome fibroblasts promotes proliferation (c). d, Overexpression of USP16 reduces the formation of neurospheres derived from human adult SVZ cells. The right panel quantifies the number of spheres in the first and second passages. P < 0.0001. All the experiments were replicated at least twice. Luc, luciferase.
a, Proliferation analysis, as well as SA-βgal and p16Ink4a staining, of three control and four Down’s syndrome (DS) human fibroblast cultures show growth impairment and senescence of Down’s syndrome cells. b, c, Lentiviral-induced overexpression of USP16 decreases the proliferation of two different control fibroblast lines (b), whereas downregulation of USP16 in Down’s syndrome fibroblasts promotes proliferation (c). d, Overexpression of USP16 reduces the formation of neurospheres derived from human adult SVZ cells. The right panel quantifies the number of spheres in the first and second passages. P < 0.0001. All the experiments were replicated at least twice. Luc, luciferase.

Conversely, when cultured cells from DS patients had their USP16 activity levels knocked down, their proliferation defects disappeared. In Clarke’s words, “This gene is clearly regulating processes that are central to aging in mice and humans, and stem cells are severely compromised. Reducing Usp16 expression gives an unambiguous rescue at the stem cell level. The fact that it’s also involved in this human disorder highlights how critical stem cells are to our well-being.”