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May 20, 2016 Research Highlight Biology

Growing a thick skin

Lab-grown skin sprouts hair and grows glands, paving the way for burn, scar and hair-loss therapies

It looks like skin. It feels like skin. It functions like skin. But the skin created at RIKEN is no ordinary outer-body tissue. Scientists at RIKEN bioengineered this skin from mouse stem cells, carefully cultivating the cells into hair, oil-producing glands and many of the other appendages found in skin1. What’s more, the elaborate organ system forms proper connections with surrounding muscles, nerve fibers and other tissues, all without yielding tumors.

The lab-made skin could one day assist in the treatment of severe burns, scars and hair-loss disorders. It may also allow drug and cosmetic companies to test the safety and efficacy of new products without relying on animals.

“We successfully regenerated a transplantable whole skin including skin appendages in mice, and confirmed their functions,” says Takashi Tsuji of the RIKEN Center for Developmental Biology, who led the study. “We think that further studies could lead to clinical applications for badly burned patients and people with severe hair loss.”

Skin in the game

Image of clumps in a collagen gel Figure 1: Clumps grown from stem cells in a collagen gel prior to be being transplanted to form specialized skin cells. 2016 © The Authors. From Ref. 1. This work is licensed under CC BY-NC

For more than a decade, Tsuji and his colleagues have been experimenting on ways to grow small organs in the lab from stem cells. They have succeeded in making teeth, hair follicles and various glands of the eye and the mouth, but until now no-one had been able to regenerate a whole organ system that combines many of these components in a single working, complex tissue.

So, Tsuji and collaborators from several Japanese institutions—including RIKEN, Tokyo University of Science, Kitasato University and Tohoku University—developed a totally new method for constructing an entire ‘integumentary’ organ, as the skin and its accessory structures are collectively known. The researchers introduced viruses into cells taken from the gums of mice. The viruses express ‘reprogramming factors’ and created induced pluripotent stem cells that, like embryonic stem cells, can form any cell type in the body. They then cultured these stem cells in the lab for 7 days so that they formed small clumps, known as embryoid bodies.

The researchers gathered dozens of these developing aggregates in a collagen gel (Fig. 1) and transplanted the gooey cellular bundles under the kidneys of mice, where they formed several types of specialized cells found in the skin. The number of hair follicles in these structures depended on exposure to a special protein that activates a signaling pathway involved in the development of hair and other organs.

After a month, Tsuji’s team extracted the cells to find three-dimensional skin, complete with shiny, black hairs and various accessory organs, including sebaceous glands that secrete an oily substance to lubricate and waterproof the skin and hair.

Just like natural hair

Image of hair from mouse stem cells Figure 2: Stem-cell-derived skin and hair follicles transplanted onto the back of a mouse. 2016 © The Authors. From Ref. 1. This work is licensed under CC BY-NC

The researchers cut out tiny skin specimens, each about the size of a grain of salt and containing about one to two dozen hair follicles, and transplanted them onto the backs of hairless mice. Within a few weeks, the scientists saw hair shafts sprouting (Fig. 2). And over the course of the three-month experiment, the hairs behaved normally, cycling through their phases with no signs of problems. “It was just like natural hair,” Tsuji says. Furthermore, anatomical analysis revealed that the tissue had correctly linked up with the underlying muscles and nerves.

The team repeated the entire experimental protocol with induced pluripotent stem cells made from stomach cells. These stem cells were engineered to glow green to allow the scientists to track them (Fig. 3). Repeating the study with stem cells reprogrammed from a different part of the body confirmed that the generation of the bioengineered integumentary organ does not depend on the origin of the cell clones.

To eliminate the risk of tissue rejection, Tsuji and his colleagues transplanted the bioengineered skin onto the backs of mice that had been genetically engineered to lack a functioning immune system. In people, however, this kind of transplant would require recipients to take immune-suppressing drugs―unless the tissue could be perfectly immune matched. This would require finding just the right donor or, by using reprogrammed stem cells, growing tailor-made skin from a patient’s own biopsied tissue.

Path to the clinic

Image of transplanted skin Figure 3: Transplanted bioengineered skin created using mouse stem cells labeled to glow green. © 2016 Takashi Tsuji, RIKEN Center for Developmental Biology

The team says their next step is to adapt the approach for clinical applications. Currently available skin grafts made by tissue engineering are generally only one or two cell layers thick and lack the support structures involved in fat secretion, moisturizing and waste excretion. They also do not aesthetically look like normal skin. A three-dimensional, complete integumentary organ offers a better alternative.

But Tsuji and his colleagues first have to ensure that the system they demonstrated with mouse cells also works with human cells. This may be more complex than it might appear, because it is not just a matter of finding the recipe for coaxing human reprogrammed stem cells to form the various appendage organs of the skin—the researchers also have to find a way to make the bioengineered skin entirely in a lab dish without relying on living animals for any step of the process.

Despite the challenges, Tsuji thinks that it is only a matter of time before he will achieve his many objectives. “We hope to begin clinical testing in humans within the next decade,” he says.

In 2008, Tsuji founded a Tokyo-based company called Organ Technologies to develop and commercialize organ replacement regenerative therapies. The Japanese drug maker Meiji Seika Pharma also recently inked a three-year deal with RIKEN to advance Tsuji’s research for human applications.

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  • 1. Takagi, R., Ishimaru, J., Sugawara, A., Toyoshima, K., Ishida, K., Ogawa, M., Sakakibara, K., Asakawa, K., Kashiwakura, A., Oshima, M. et al. Bioengineering a 3D integumentary organ system from iPS cells using an in vivo transplantation model. Science Advances 2, e1500887 (2016). doi: 10.1126/sciadv.1500887

About the Researcher

Takashi Tsuji

Image of Tsuji Takashi

Takashi Tsuji received his master’s degree from Niigata University in 1986. After working in the pharmaceuticals industry for three years, he returned to the university to complete his doctorate degree in 1992 and continue working as a researcher. Tsuji joined Japan Tobacco Inc. in 1994 and moved to Tokyo University of Science in 2001, where he was appointed a full professor in 2007. In 2014, Tsuji joined the RIKEN Center for Developmental Biology, where he leads a team working to gain a more complete understanding of the role of epithelial–mesenchymal interaction in organ induction, development and morphogenesis. His team seeks to apply their research toward the development of technologies for use in therapeutic organ regeneration.