Shaun of the Dead: Reprogramming Skin Epithelial Cells

Shaun is in his 30s, works at an electronics store, and lives with his best friend, Ed, in a small flat in London. His dull existence unexpectedly becomes an adventure as zombies invade the town. His girlfriend, Liz, cares deeply for Shaun but desperately wants Shaun to grow up. The town becomes overrun with zombies which forces Shaun to rise to the occasion to protect Liz, his mother, and friends.

INTRODUCTION:

The average life expectancy of the worlds’ population continues to rise and the need to heal ulcers will also become more increasingly common. Large cutaneous ulcers tend to be life-threatening and today’s treatment options involve transplanting pre-existing epithelial regions such as skin grafts or applying cultured cells into patients' therapy. Developments in alternative supplies in epidermal coverage for skin treatment for wounds and expanding epithelial tissues using in-vivo reprogramming of wound-resident mesenchymal cells exist thanks to researchers. [C]

Researchers from Salk Institute of La Jolla, California have discovered that they can treat surface wounds on patients from the inside out. These studies, led by Carlos Izpisua Belmonte, revealed that they could turn wounded skin cells into healing surface skin cells. Their observations are pioneering a path for developing simple, non-surgical treatments for wounds in patients. [A]

Transduction of four transcription factors that specify the skin-cell lineage enabled efficient and rapid de-novo-epithelialization from the surface of cutaneous ulcers in mice. These findings may provide a new therapeutic avenue for treating skin wounds and could be extended to other disease situations in which tissue homeostasis and repair are impaired. [C]

BACKGROUND INFORMATION:

Our skin is our largest organ and most important one because it protects us from outside foes. Skin also helps to regulate the body’s temperature and allows for sensations like touch, heat, and cold to be felt. The skin consists of a total of 3 layers: the epidermis, dermis, and deep subcutaneous tissue or ‘hypo-dermis’. The outermost layer is the epidermis and it is a waterproof barrier and gives everyone their unique skin tone. [B]

Melanocytes are the special cells that give skin it’s color. These melanocytes produce the pigment melanin. Underneath this layer is the dermis which contains touch connective tissue, hair follicles, and sweat glands. The deepest layer of skin is the hypodermis which is made up of fat and connective tissue. [B]

Some common skin conditions include skin rashes where the skin changes in appearance, are caused from simple skin irritations and result of medical conditions. these conditions are known as eczema. this is a skin inflammation that causes itchy rashes due to an overactive immune system. Then there is psoriasis which is an autoimmune condition that causes a variety of skin rashes. Finally, there is dandruff, a condition that is most likely caused by seborrheic dermatitis, psoriasis, or eczema. Other common skin conditions include acne, cellulitis, skin abscesses-boil or furuncle-, rosacea, warts, and melanoma. [B]

When repairing damaged skin cells, it is crucial for the migration of keratinocytes from the adjacent epidermis to travel into the wound to promote re-epithelialization. however, in cases of larger wounds, this step in the healing process is not effective. Thus, in order to improve patient outcomes, more rapid and efficient methods for regenerating epidermal coverage must be developed, preferably non-surgical interventions. [C] 

Routine skin tests such as skin biopsy, skin testing (allergy tests, i.e. pollen), and tuberculosis skin test (‘purified protein derivative’ or ‘PPD’). Skin Treatments such as ‘cortical-sterioids’ (Skin treatment for steroids: Medicines that reduce immune system activity may improve dermatitis. Aside from topical steroids (which are most often used), antibiotics, antiviral drugs, anti-fungal drugs and antihistamines, Skin Surgery, Immune Modulators, and Skin Moisturizers can also help. [B]

When the surface of the skin is ruptured, epithelial cells (outer layer of the skin), migrate to the wound to seal up the injury. This healing process becomes more difficult in larger wounds and is impaired in older people, making the need for simple, effective treatments all the greater. So, in cases where patients have large skin wounds or ulcers that are both painful and even life-threatening, these breakthroughs are so important in improving quality of life. [A]

RESEARCH:

After recent advances in cellular reprogramming, it became apparent that wound-resident cells could be reprogrammed towards an epidermal progenitor cell fate to generate new epithelial cells, thereby promoting de-nova-epithelialization from the surface of a cutaneous ulcer. [C]

The initial approach was to reprogram mesenchymal cells (or 'Human Dermal Fibroblasts') and adipose-derived stromal cells that participate in wound healing. By comparing gene expression profiles of human keratinocytes and primary HDF's, upstream promoter analysis, and gene expression reversal analysis, 55 transcription factors were identified and 31 microRNAs that are potentially involved in keratinocyte specification. [C]

 

The study involved using the genetic technique known as ‘cellular reprogramming’ to change non-epithelial cells in wounds. Viruses were injected into the cells of non-healing ulcers which forced the expression of 4 genes in these other, non-epithelial skin cell types to change into epithelial cells. These newly formed epithelial cells then successfully healed injuries in mice over a 28-day period or in other cases, less. [A]

These candidates were further tested by assessing expression levels after calcium-induced differentiation of keratinocytes and by transducing each candidate into hDFs and measuring the levels of the keratinocyte markers, keratin 14 (KRT14) and cadherin. Selected factors were then co-transduced (via lentivirus) in different combinations into hDFs and the generation of keratinocyte-like cells was assessed. A combination of 28 transcription factors generated keratinocyte-like cells in vitro. When these cells were grown in 3D organotypic culture, they formed a stratified epithelium. We therefore named these cells 28TF-induced stratified epithelial progenitors. [C] The study is published in the scientific journal ‘nature’ for those who want a more detailed explanation of these results. [A]

CONCLUSION:

Major improvements in technology, more tests are needed to support these observations and to ensure long-term results, success, and safety for human patients. The team as well as Belmonte are optimistic for the study’s future. If this technology could help treat chronic ulcers in humans, it could be a simpler and quicker solution than surgical skin transplants or artificial skin grafts. If this method should prove to be successful beginning with the epidermis (human skin) then scientists can move on to using this repair method to other tissues and organs. [A]

Treatment would most likely be categorized as a form of gene therapy and it would be delivered through ‘local introduction of viruses to reprogram the very cells located in the wound or ulcer.’ Unfortunately producing viruses tend to be quite expensive, but they should be less of an issue if researchers and scientists were able to scale up the production of viruses. [A]

LINKS:

[A] https://www.theguardian.com/science/2018/sep/05/scientists-find-way-of-treating-skin-wounds-without-surgery

[B] https://www.webmd.com/skin-problems-and-treatments/picture-of-the-skin#1

[C] https://www.nature.com/articles/s41586-018-0477-4

[D] http://www.leavemethewhite.com/caps/thumbnails.php?album=230&page=5

[E] https://film-grab.com/2010/09/13/shaun-of-the-dead/

*Please note! These images are not mine. They were found on various tumblr, pinterest, google image sites! If any are yours’, please let me know so that I can give you credit for them! Also, the people in the images have no relation to the diseases, illnesses, or cancers I write about. Thanks so much & enjoy~