Behind the hype in stem cell therapy

True therapeutic application of stem cells in dermatology is a tapestry of hope, promising early studies and false claims. While stem cells are showing promise in areas such as wound healing and in the treatment of skin fragility from epidermolysis bullosa, their use in heavily promoted topical antiaging preparations is, by our experts’ accounts, nowhere near ready for prime time.

Dr. GeronemusRoy G. Geronemus, M.D., chairman of the board of the New York Stem Cell Foundation, the largest stem cell research program in the country, says he strongly believes in the present and future of the clinical use of stem cells.

“I do, however, urge caution and restraint in reference to the commercial claims regarding the potential efficacy of stem cells in dermatology at this point in time. As for cosmetic dermatology, it has been well proven that adipose tissue is a rich source of stem cells, and this likely explains the sustained benefit seen with fat transfer for volume replacement. Blood or plasma are also sources of stem cells leading to potential benefit of [platelet-rich plasma] PRP in cosmetic dermatology for rejuvenation and healing, although well controlled studies are needed to establish efficacy. Data on the use of stem cells applied topically in commercial creams is minimal, and its benefit has not yet established.”

The field of dermatology, Dr. Geronemus says, will likely benefit from research underway with Induced pluripotent stem cells, also known as iPScells or iPSCs.

“These cells (taken from skin biopsies) can be grown and differentiated into almost any disease and subsequently used to evaluate the potential efficacy of new drugs and also used to predict drug toxicity,” Dr. Geronemus says.

Lots of hype, little substance for stem cells in topicals

“Stem cells don’t work in topical antiaging creams and treatments,” is the headline in a recent Miami Herald column,¹ by Miami, Fla.-based dermatologist Leslie Baumann, M.D., CEO of Baumann Cosmetic and Research Institute. Dr. Baumann runs Skin Type Solutions Franchise Systems LLC, a dermatologist-developed resource that provides skin care education for dermatologists, their patients and their staff.

“It makes me sad when I see a dermatologist promoting stem cell products, because we need to be the expert resource on skincare that our patients can trust,” Dr. Baumann tells Dermatology Times. “I posted my newspaper column … and asked dermatologists to tell me if they agreed with it. About 60 of them said yes and none said no. That tells me that most dermatologists-or at least the ones that are my Facebook friends-understand that stem cells in topical products are worthless.”

Plant-based stem cells are simply too large to penetrate the skin and cannot live in the cream while it stays on the shelf for months or even years, Dr. Baumann says.

Dr. HopeDermatologist Richard Hope, M.D., of Lubbock Dermatology and Skin Cancer Center, in Lubbock, Texas, agrees.

“I believe the current use of ‘stem cells’ in topical skincare products is of no value at this point. The ‘stem cells’ are plant derived, dead and basically have no activity in human skin. This is marketing to a poorly informed public,” Dr. Hope says.

But there is hope, according to Dr. Hope, when one looks beyond manufactured topicals.

 “Human stem cells will likely have an impact on skin rejuvenation and hair restoration. Probably similar to how PRP (protein rich plasma) is used today,” Dr. Hope says. “These will be cosmetic procedures and not likely to be in topical skincare regimens, as the stem cells need to be harvested from the patient, and they do not directly penetrate the epidermis.”

Read more: Stem cells generate hair growth

Next: Where the science looks strong

Where the science looks strong

Dr. BowersAngela Bowers, M.D. of Southlake Dermatology, Southlake Texas, says that while there isn’t a physical or chemical way to make stem cells penetrate the skin that actually works, there are ways in which to stimulate these cells.

“However, there is a novel new cosmetic product that uses defensins to stimulate our stem cells at the bulge of our hair follicles. The product is called Defenage [Progenitor Biologics] and has shown incredible results for our patients,” Dr. Bowers says. “I believe this is the next biggest game-changer in topical products for anti-aging, wound healing and a variety of other skin diseases and conditions.”

Amy Forman Taub, M.D., medical director, founder of Advanced Dermatology/skinfo.com, in Lincolnshire, Ill., and assistant clinical professor of dermatology at Northwestern University Medical School, Chicago, is among the researchers for Defenage. She says that to understand the basic cosmeceutical application of stem cells and how they regulate biological activity within the skin, dermatologists must first understand that there is no such thing as “generic” stem cell batch.

“Similar to people discussing curing cancer, as if it were all one illness, there are a myriad of different stem cell types,” Dr. Taub says. “Scientists from various groups have identified at least 10 stem cell types that reside within the hair follicle, although not all of them stimulate hair growth. Specifically one, the LGR6+ stem cell, is targeted by Defenage, the new skincare product. Subsequent to application of this topical product on the skin, this LGR6+ stem cell is stimulated to increase production of new keratinocytes.

LGR6+ usually springs into action after we have experienced a cut or scrape, a reparative mechanism.”

This is a paradigm shift away from the application of a “soup” of multiple different growth factors to the targeting of one or multiple specific pathways of growth within the body.

“This change in thought reminds me of the shift from generalized reduction of the immune system with methotrexate or cyclosporine for psoriasis and toward specific receptor blockage in the aberrant biochemical pathway,” Dr. Taub says. “Hair growth is a very complex biological process in which there are probably four to 10 factors that play a role at any given time. If we could target the specific molecules responsible for the pathways leading to the signal to hair follicles to change from a telogen hair to an anagen hair, then we would be closer to growing hair. PRP has been very popular but does depend on the older paradigm of flooding the tissue with intact growth factors (e.g., those in the serum) and hoping these native proteins or peptides will trigger growth. Newer technology will use biomimetic or manufactured peptides that are specific for multiple pathways and will be used simultaneously to turn on growth.”

Related: Cosmeceutical contains multipotent growth factor

Healing burns

An investigational product in phase 2 studies and seeking FDA clearance is the RenovaCare SkinGun, a technology that sprays a patient’s stem cells back onto burned tissue. The technology has been shown in early research to regenerate new skin in as little as four days.

Dr. SimmanRichard Simman, M.D., a plastic and reconstructive surgeon, professor at Wright State University Boonshoft School of Medicine and founding president and chair of the American Board of Wound Medicine and Surgery, says the stem-cell based treatment could result in faster healing of burns and wounds in general.

“When you achieve faster healing, you have less scar formation. This will result in better functional and cosmetic outcomes,” says Dr. Simman, who is on the RenovaCare advisory board.

Scientists learned how to harvest and isolate epithelial stem cells to treat burn patients’ skin as early as the 1970s and 1980s. This technology is based on in-vitro culture, expansion and sheets production of patients’ keratinocytes. The expensive process involves sending the patient’s skin sample to specialized labs and requires three to four weeks before the sheets are available for clinical use, according to Dr. Simman.

“What’s unique about our technology is that the isolation and preparation process takes place on the spot,” he says. “With minimal manipulation of the stem cells, they are isolated from the patient’s own skin, they’re suspended in a medium then they are gently and evenly sprayed on the patient’s prepared wound bed, using the SkinGun. After engraftment, these stem cells will take and start forming islands. These islands quickly reach confluence and cover the wound to achieve rapid healing.”

So far, the investigational technology has been studied on more than 60 patients with deep second-degree (partial thickness) burns in the U.S. and Germany. The process saves patients the pain of daily dressing changes, offers the possibility of faster healing at potentially much lesser cost and has yet to show any downsides, according to Dr. Simman.

New hope for EB?

Dr. KirkorianUse of induced pluripotent stem cells, iPSCs, which are created from a patient's own fibroblasts or keratinocytes, might someday offer new hope in the treatment of epidermolysis bullosa (EB), according to A. Yasmine Kirkorian, M.D., assistant professor of dermatology and pediatrics, Children's National Health System, George Washington University School of Medicine and Health Sciences, Washington, D.C.

“Fibroblasts and keratinocytes are harvested from the patient and made into iPSCs. Using various methods of gene editing, the normal COL7A1 gene is inserted into these iPSCs, which can then be injected back into the mouse model or they can be turned back into keratinocytes and used to make a kind of skin graft that can be applied to the patient. Another method is to take naturally-occurring revertant mosaic areas of skin … and make iPSCs, which are then made into larger ‘skin graft-like’ organoids that can be applied back to the patient,” Dr. Kirkorian says. “These grafts are temporary in nature but attractive in concept because they would not be rejected as a transplant, since they are created from the patient's own cells.”

Another strategy for using stem cells to treat EB patients uses mesenchymal stromal/stem cells, which are derived from bone marrow or umbilical cord blood.

“When these are injected into the skin of mice, they express type VII collagen, which can help to restore skin adhesion temporarily,” Dr. Kirkorian says. “Mesenchymal stromal/stem cells have been used in a randomized-controlled trial in 14 patients with [recessive dystrophic (RD) EB] with some promising results. Finally, there was a small clinical trial of bone marrow transplantation in patients with RDEB. Seven patients were selected but only six were transplanted because one died of cardiomyopathy before transplant. One died of complications of the transplantation regimen. The remaining patients did have evidence of increased collagen VII, although this approach is challenging given the morbidity of transplant regimens in already fragile patients.

The bottom line, Dr. Kirkorian says, is that there are exciting strategies that could temporarily or permanently improve skin fragility in these children, but the strategies are not yet ready for prime time.

“Concerns include that the stem cells in some trials are generated using retroviruses, which have risks include cancer formation and other unanticipated outcomes. Many of the skin equivalents that have been created have only temporary benefit,” Dr. Kirkorian says. “As gene editing techniques are developed that are not dependent on retroviruses and can precisely repair the affected gene with durable results, this may prove a life-altering or life-saving treatment for these very unfortunate children and adults.”

EB: Hope for butterfly children

Next: Looking to the future

So, when?

It could be years before dermatology sees an approved stem cell treatment for any indication.

Dr. Baumann says that might be 20 years before there’s a topical stem cell therapy that really works to rejuvenate aging skin.

“In the meantime, I believe that using topical ingredients like retinoids, glycolic acid, growth factors and defensins to influence stem cells is still the way to go,” Dr. Baumann says.

And she thinks injectable stem cell therapy for skin rejuvenation is more than a decade away from making it to market.

“It takes at least seven years to get through the FDA and, as far as I know, safe technology to inject stem cells to improve the skin’s appearance is not invented yet,” Dr. Baumann says. “Hopefully they will solve this puzzle in the next 20 years because I’m getting older every day!”

For more on the topic

Stimulation of the follicular bulge LGR5+ and LGR6+ stem cells with the gut-derived human alpha defensin 5 results in decreased bacterial presence, enhanced wound healing, and hair growth from tissues devoid of adnexal structures

Lough D, Dai H, Yang M, Reichensperger J, Cox L, Harrison C, Neumeister MW. Stimulation of the follicular bulge LGR5+ and LGR6+ stem cells with the gut-derived human alpha defensin 5 results in decreased bacterial presence, enhanced wound healing, and hair growth from tissues devoid of adnexal structures. Plast Reconstr Surg. 2013 Nov;132(5):1159-71. http://www.ncbi.nlm.nih.gov/pubmed/?term=Stimulation+of+the+Follicular+Bulge+LGR5%2B

The hair follicle-a stem cell zoo. (review)

Jaks V, Kasper M, Toftgård R. The hair follicle-a stem cell zoo. Exp Cell Res. 2010 May 1;316(8):1422-8. doi: 10.1016/j.yexcr.2010.03.014. Epub 2010 Mar 23. Review. http://www.ncbi.nlm.nih.gov/pubmed/?term=The+hair+follicle%E2%80%94a+stem+cell+zoo

Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin.

Snippert HJ, Haegebarth A, Kasper M, Jaks V, van Es JH, Barker N, van de Wetering M, van den Born M, Begthel H, Vries RG, Stange DE, Toftgård R, Clevers H. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science. 2010 Mar 12;327(5971):1385-9.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lgr6+Marks+Stem+Cells+in+the+Hair+Follicle+That+Generate+All+Cell

Epithelial stem cells and implications for wound repair

Plikus MV, Gay DL, Treffeisen E, Wang A, Supapannachart RJ, Cotsarelis G.Epithelial stem cells and implications for wound repair. Semin Cell Dev Biol. 2012 Dec;23(9):946-53. http://www.ncbi.nlm.nih.gov/pubmed/23085626

Disclosures: Dr. Geronemus, Dr. Bowers, Dr. Hope, and Dr. Kirkorian report no relevant disclosures. Dr. Bowers has a financial interest in Progenitor, which owns Defenage. Dr. Taub is on the Medical Advisory Board of MediCell Technologies, does paid research and owns a small amount of stock. Dr. Simman is on the RenovaCare advisory board.

References:

1.      http://www.miamiherald.com/living/health-fitness/skin-deep/article62053467.html