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.”