Saving Your Skin

Monday, December 11, 2017

In 2015, a seven-year old boy in Germany lost 60% of his skin due to a genetic disorder. Miraculously, after all conventional treatments had failed and he was nearing death, engineered skin cells were able to promote regrowth of his skin.

Junctional epidermolysis bullosa (JEB) is a genetic disorder that impacts how the epidermis, the top layer of the skin, connects to the deeper layer of the skin, the dermis. This faulty skin connection leads to blisters and massive chronic skin wounds, which leave patients open to infections and an increased risk of skin cancer.

JEB is often lethal, but researchers from Germany and Italy used a novel take on existing skin-repairing surgery to save the boy’s life. This research was published in Nature in mid-November.

Currently, skin grafting surgical techniques exist to help patients who have lost large areas of skin due to accident or disease, like those who have received severe burns. Sometimes skin is harvested from other, healthy skin on the patient, or surgeons use sheets of epidermis that have been created in a laboratory.

Because the boy had a mutation in LAMB3, one of several genes important in connecting the epidermis to the dermis, he had no properly functioning skin to harvest for surgery. Instead, scientists derived keratinocytes, the predominant cell type in the epidermis, from a skin biopsy from the boy. They introduced a normal, functioning copy of the gene LAMB3 into the keratinocytes using a virus.

Viral-mediated gene integration is a common laboratory technique that takes advantage of the normal functions of some families of viruses. Viruses cannot make proteins, the functional output of their genomic information, on their own. Instead, some viruses insert their genes into their host’s genome, and use the host’s cell machinery to generate the proteins necessary for survival. Viruses can be modified to carry only a gene sequence of interest, like LAMB3, which they then integrate into the genome of the cell they are exposed to, like keratinocytes.

Some of the keratinocytes expressing functional LAMB3 were grown on plastic, while others were grown on a special protein substrate known to help skin cells grown in the lab, called fibrin. The cells were grown to form epidermal sheets and were surgically grafted onto the boy’s skin.

Both cells grown on plastic and fibrin regenerated the boy’s skin after one month. The grafted skin was able to grow, spread, and heal other wounds on his body, eventually regenerating 80% of the boy’s total body surface area.

After 21 months, the genetically engineered, lab-grown skin appeared normal, both under a microscope and by eye.

Furthermore, the boy’s regenerated skin was only comprised of cells expressing LAMB3, and no evidence of toxicity or insertion into genes that may lead to cancer was found.

While the cells derived from the boy’s skin biopsy were predominantly keratinocytes, some of the cells in the culture were long-lived stem cells, called holoclones. These holoclones, modified with LAMB3, gave rise to the mature keratinocytes in the lab-grown epidermis and sustained it post-surgery.

Although this study focused on skin, this technique of modifying long-lived stem cells may have implications for regeneration of other organs. Growing organs in the lab from modified, patient-derived stem cell populations would increase the availability of organs for transplantation and reduce the risk of rejection by the host body. The key to making this kind of advance possible is identifying the population(s) of long-lived stem cells capable of regenerating an entire organ, and then optimizing how to grow them in the laboratory.