More than 100 million individuals worldwide are affected by Psoriasis
a skin disorder. Its economic impact is more than $10 billion annually in the U.S. alone. Affected skin becomes thickened, red, and covered with silvery scales, while changes to the nails and deforming inflammation of the joints may also occur in up to one-third of affected individuals. The underlying cause of psoriasis
remains a mystery, and effective targeted therapies remain to be developed.
Researchers from Brigham and Women's Hospital and the Harvard Stem Cell Institute have uncovered a novel pathway that may explain why skin thickens in psoriasis
and suggests new strategies for developing therapies for the condition.
The team's results are published in the Journal of Investigative Dermatology
Dr George Murphy, MD, director of the Program in Dermatopathology in the Department of Pathology at the Brigham and co-senior author told Thailand Medical
places social and psychological stress on patients and is associated with risk of diabetes
, cardiovascular disease and more. While steroids and biologics can be prescribed, we don't have a cure because we haven't understood the cause. Our initial finding that skin thickening in psoriasis is due to build-up of dysregulated stem cells and their progeny are exciting because it represents a new way of thinking about an old and significant skin disease."
To discover the basis for the dysregulated skin stem cell behavior, the investigators focused on the epigenome, the methylated wrapping that covers each DNA strand and orchestrates how individual genes behave.
Dr Christine Lian, MD, a dermatopathologist in the Department of Pathology at the Brigham commented, "Without understanding the mechanism underlying a disease, it's hard to find effective treatments. The question we decided to pursue was: Is there an epigenetic abnormality in psoriasis that may explain why stem cells are misbehaving?"
Dr Lian, Dr Murphy and their colleagues found a defect in the epigenetic covering that resulted in the loss of a DNA methylation hydroxymethylation mark.
Known as loss of 5-hmC
, this defect was found in cells from patients with psoriasis but not other skin conditions that produce a similar skin thickening, such as callous-like areas from chronic irritation. The team replicated the defect in a mouse model of psoriasis and found that it preferentially affected genes that regulated the function of skin cells.
Dr Lian and Dr Murphy have previously shown that 5-hmC
loss in the skin epigenome can be reprogrammed using agents as fundamental as ascorbic acid (vitamin C
). They reasoned that therapeutic correction of the epigenomic defect in psoriasis
might reverse the entire process. Based on experiments using skin stem cell cultures in the lab, the team presents promising preliminary data suggesting that 5-hmC
levels can be restored to correct the deficiency seen in psoriasis
The researchers note that while there is much interest in the role of vitamin C
, additional research is needed to develop and test effective treatments since simply taking a vitamin supplement might only have little effect for some.
The research team has begun work on the next research steps, which will involve three-dimensional bioprinting of skin stem cells in the context of their supportive niches to test other epigenetic reprogramming agents.
Dr Murphy added, "If successful, our epigenetic stem cell explanation for psoriasis hopefully could transform therapy, allowing for more personalized and targeted approaches directed at the very cells that accumulate to form the heartbreak of this all-too-often devastating skin condition.”
Reference: Loss of the Epigenetic Mark, 5-hmC, in Psoriasis: Implications for Epidermal Stem Cell Dysregulation Feng Li ,Christine W. Yuan ,Shuyun Xu ,Tingjian Zu ,Yvon Woappi ,Catherine A.A. Lee ,Phammela Abarzua, Michael Wells , Matthew R. Ramsey , Natasha Y. Frank , Xunwei Wu , Anna Mandinova , Markus H. Frank , Christine G. Lian ,George F. Murphy , Journal of Investigative Dermatology, Published : Dec 11, 2019