How Stem Cells Make New Skin Cells Throughout Life


Beneath the upper epidermal layers of our skin lies a layer of stem cells and their progeny (human epidermal progenitor cells) that continually make new skin throughout our lifetime. How these stem cells manage to form skin and not some other structure is still poorly understood, but a new study from the University of San Diego School of Medicine in the laboratory of George L. Sen has pulled back the curtain on this vital process.

Sen and his colleagues have examined a component of the machinery of the cell known as the “exosome.” The term exosome is confusing because it refers to two different entities. Exosomes are vesicles secreted by cells that are loaded with proteins and RNA molecules that the cell wants to dump (Kooijmans, et al., Int J Nanomedicine. 2012; 7: 1525–41). Exosomes are used by cells to export materials to other others cells. Cells also use exosomes to regulate processes, since by ridding themselves of proteins and RNAs that direct particular processes, effectively shuts those processes down. However, exosome also refers to a complex of proteins that are involved in 3′–5′ exonucleolytic degradation. This exosome consists of ~11 proteins that degrade RNAs and regulate processes.

In skin-based stem cells, the exosome (RNA degradation machinery) functions in skin stem cells and provides one of the main mechanisms by which stem cells stay stem cells and skin cells stay skin cells. Exosomes and their targets may help point the way to new drugs or therapies for not just skin diseases, but other disorders in which stem and progenitor cell populations are affected.

Stem cells can divide throughout their lifetime, and their progeny can differentiate to become any required cell type. The progeny of stem cells, progenitor cells, have more limited developmental capabilities, and are only able to divide only a fixed number of times and form a few distinct cell types. When it comes to skin, progenitor and stem cells deep in the epidermis constantly produce new skin cells called keratinocytes that gradually rise to the surface where they will mature, die, and be sloughed off.

Exosomes degrade and recycle different RNA molecules, such as messenger RNAs that wear out or that contain errors. Such errors would cause the production of junk protein, and this would be deleterious to the cell.

According to Sen: “In short, the exosome functions as a surveillance system in cells to regulate the normal turnover of RNAs as well as to destroy RNAs with errors in them.” Sen and his colleagues discovered that in the epidermis the exosome functions to target and destroy mRNAs that encode for transcription factors that induce differentiation. One of the targets of the exosome in epidermal progenitor cells is a transcription factor called GRHL3. GRHL3 promotes the expression of genes necessary for skin cell differentiation. Routine destruction of GRHL3 keeps epidermal progenitor cells undifferentiated. When the epidermal progenitor cells receive signals to differentiate, the progenitor cells down-regulate the expression of certain subunits of the exosome, and this leads to higher levels of GRHL3 protein. The increase in GRHL3 levels promotes the differentiation of the progenitor cells to skin cells.

“Without a functioning exosome in progenitor cells,” said Sen, “the progenitor cells prematurely differentiate due to increased levels of GRHL3 resulting in loss of epidermal tissue over time.” Sen also noted that these findings could have particular relevance if future research determines that mutations in exosome genes are linked to skin disorders or other diseases.

“Recently there was a study showing that recessive mutations in a subunit of the exosome complex can lead to pontocerebellar hypoplasia, a rare neurological disorder characterized by impaired development or atrophy of parts of the brain,” said Sen. “This may potentially be due to loss of progenitor cells. Once mutations in exosome complex genes are identified in either skin diseases or other diseases like pontocerebellar hypoplasia, it may be possible to design drugs targeting these defects.”

Huntington’s Disease Model System Derived from Patient-Specific Induced Pluripotent Stem Cells


Huntington’s Chorea or Huntington’s disease is an inherited condition that results from the progressive and relentless degeneration of nerve cells in the central nervous system.  Huntington’s disease (HD) broadly affects the patient’s functional abilities and decreases his or her ability to move, think or behave properly.  Most of the time, patients develop the signs or symptoms of HD when they are 40 or 50 years old or slightly older.  In the case of Juvenile HD, symptoms begin before the age of 20.

Mutations in the HTT gene, which encodes the Huntingtin protein cause HD, and typically, the mutations in the gene that are associated with HD are so-called “triplet expansions.”  To understand triplet expansions, we must understand how genes encode proteins.  Genes are stretches of a DNA molecule that are transcribed into RNA copies.  The enzyme that synthesizes the RNA copy is called RNA polymerase, and a gene has a set of sequences that tell the RNA polymerase where to start making RNA copies and where to stop.  Once the RNA copy of the stretch of DNA is made, the RNA either has a function of its own, or the RNA is translated into protein.  Translation is the process by with RNA-protein complexes called “ribosomes” bind to the front of the RNA and use the nucleotide sequence to synthesize a protein that has a specific sequence of amino acids.  Amino acids are encoded in genes by a three-nucleotide sequence or codon, and ribosomes read the RNA molecules three nucleotides at a time.

The nucleotide sequence CAG (cytosine, adenine, guanine) encodes the amino acid glutamine.  The HTT gene has a stretch of these nucleotides, and they code for the amino acid glutamine.  Normal copies of the HTT gene will have anyways from nine to thirty-five glutamines in these stretches.  However, these CAG stretches have a tendency to expand because the enzymes that replicate DNA (DNA polymerases) have a tendency to slip when they get to CAG stretches, and this causes the CAG stretches to increase in size, or, occasionally, decrease in size.  The glutamine stretches can reach large numbers, and if the number of glutamines in the glutamine stretch exceeds 35, people will usually start showing symptoms.  The larger the number of glutamines in the glutamine stretches, the earlier the symptoms will appear (Juvenile HD usually occurs in patients with 60 or more glutamines in the glutamine stretch), and the more aggressive the disease.

How does the abnormal Huntingtin protein kill nerve cells?  This is unclear, but it is clear that Huntingtin proteins with abnormally large numbers of glutamines in their glutamine stretches are poisonous to cells, and the nerve cells that die tend to dump their neurotransmitters, which kills other nearby cells, which then cause them to dump their neurotransmitters, and the cascade of cell death begins.

Cell transplantation experiments in animals have produced a variety of positive results, but these results are probably not representative of the situation in human patients.  HD in animals, you see, is induced by the injection of chemicals into the brains of laboratory animals, and these chemicals kill off particular groups of nerve cells that cause the symptoms of the disease.  The rest of the brain is essentially normal.  Human patients have a brain that has been transformed into a toxic waste dump, and transplanted cells do not survive well in them.  I have other blogs on this site that speak about this here, here, and here.

To address this problem, a South Korean group has developed a model system for HD based on induced pluripotent stem cells made from an actual HD patient.  This paper was published in the journal Stem Cells on May 24, 2012 (doi: 10.1002/stem.1135), and is entitled:  Neuronal Properties, In Vivo Effects and Pathology of a Huntington’s Disease Patient-Derived Induced Pluripotent Stem Cells.  The lead author is I. Jeon from the CHA Stem Cell Institute, CHA University, Seoul, Korea.

In this paper, Jeon and colleagues took skin cells from HD patients and used them to make induced pluripotent stem cells (iPSCs).  By carefully manipulating the cells in culture, the South Korean scientists were able to convert the iPSCs into nerve cells.  The particular patient whose IPSCs were used in this experiment had a HTT gene that encoded a Huntington protein with 72 glutamines and the patient had a juvenile form of HD.

The specific nerve cells that degenerate in the brains of HD patients are neuron that produce the neurotransmitter GABA (gamma-amino butyric acid).  Therefore, Jeon and his coworkers had GABA-specific neurons from the iPSCs.  WHile the initial induction rate for nerve cell production from the iPSCs from the HD patient was low, they were able to produce a respectable quantity of GABA-neurons from the HD iPSCs.

Nest, they took rats and generated the types of lesions necessary to cause HD, but they transplanted the GABA-neurons that were made from the HD-iPSCs into the brains of the lesioned rats.  Interestingly, the rats recovered from the lesions and their behavior returned to normal.  At 12 weeks after the transplantations, the brains of the rats still looked normal.

However, once the rats were treated with a chemical that prevents cells from getting rid of excessive amounts of junk proteins, now the rats started to show the symptoms of HD and their brains showed pathologies that greatly resembled those found in HD patients.  Also, if the GABA neurons made from the HD iPSCs were implanted into the brains of neonatal rats, which grow very quickly, they produce HD-like pathology 33 weeks after transplantation.

What does this mean?  Even though these rats carried GABA neurons that contained a severe version of the HTT gene, the neurons still were able to work and give rise to normal neurons inside the body of the animals.  However, those animals were extremely susceptible to any sort of perturbations that caused junk proteins to build up.  If the levels of junk protein built up, they eventually killed the cells.  What are those triggers in human patients that cause cells to clog up with junk proteins?  Clearly this HD model will help neuroscience researchers answer some very vital questions about the cause and pathology of HD.  Answers that might lead to efficacious treatments that will reduce the extreme suffering of some patients.