Tag: keratinocytes

Categories : DermatologyTags : Leave a comment

Starvation and Adhesion Drive Formation of Keratinocyte Patterns in Skin

On By ModernMedia
Skin cell (keratinocyte) This normal human skin cell was treated with a growth factor that triggered the formation of specialised protein structures that enable the cell to move. We depend on cell movement for such basic functions as wound healing and launching an immune response. Credit: Torsten Wittmann, University of California, San Francisco

Fingerprints are one of the best-recognised examples of pattern formation by epithelial cells. The primary cells in the epithelium are the keratinocytes, and they are known to form patterns at the microscopic and macroscopic levels. While factors affecting this pattern formation have been reported, the exact mechanisms underlying the process are still not fully understood.

A team of researchers, led by Associate Professor Ken Natsuga at the Faculty of Medicine, Hokkaido University, have revealed that cell-cell adhesion governs pattern formation in keratinocytes. Their findings were published in the journal Life Science Alliance.

“In this study, we used an immortalised keratinocyte cell line, called HaCaT, which retains all the properties of normal keratinocytes,” Natsuga explained. “In order to ensure that our findings were accurate, we established single-cell cultures from this cell line.”

The team observed pattern formation in both the original heterogeneous cell line, as well as in single-cell-derived cultures. During culturing, the keratinocytes moved randomly and spontaneously formed high- and low-density regions, leading to pattern formation.

The pattern formation was markedly influenced by starvation. When the culture medium was renewed, patterns were obscured, but reappeared as the nutrients in the culture medium were consumed by the keratinocytes.

The team then examined the gene expression in the keratinocytes, which revealed that cell adhesion proteins and keratinocyte differentiation proteins were upregulated in high-density regions. “As cell adhesion is necessary for the development of high-cell-density regions, we specifically investigated the expression of adherens junction (AJ) molecules such as E-cadherin and actin,” Natsuga elaborated. “We found that these molecules were localised at the intercellular junctions of high-density regions.”

The authors then used a mathematical model to confirm that, under spatially uniform density and stress, strong cell adhesion leads to the formation of density patterns. They were also able to demonstrate that the keratinocyte patterns influenced cell proliferation and differentiation, and that serum starvation influences epidermal stratification (a type of differentiation) in skin cells from mice.

“Our study presents a novel and robust model of cell–cell adhesion-induced patterning (CAIP),” concludes Natsuga. “We have deepened our mechanistic insight into cellular organization and its consequences for cell fate decisions and epithelial stratification.”  The team demonstrated that epithelial cell–cell adhesion is essential and sufficient for patterning. Future work will focus on adding more variables to the model to understand other processes that occur concurrently during development.

Source: Hokkaido University

Categories : DermatologyTags :

Exploring the Mechanism behind Drug Eruptions in the Skin

On By ModernMedia
Skin cell (keratinocyte). This normal human skin cell was treated with a growth factor that triggered the formation of specialised protein structures that enable the cell to move. We depend on cell movement for such basic functions as wound healing and launching an immune response.
Credit: Torsten Wittmann, University of California, San Francisco

Millions of people worldwide suffer from unpredictable drug toxicities every year. In particular, drug eruptions which manifest through symptoms such as redness, blisters, and itching on the skin, are quite common. Severe drug eruptions can become life-threatening and can have long-lasting consequences.

Previous studies have identified specific variants of certain genes as potential causal agents of drug eruptions. Scientists believe that the genes encoding the human leukocyte antigen (HLA), a protein expressed on the surface of leucocytes known to play an important role in the immune system, are involved in the onset of drug eruption. But current theories cannot explain why HLA-related drug eruptions typically manifest on the skin rather than in multiple organs throughout the body.

To address this knowledge gap, a research team including Lecturer Shigeki Aoki, Kousei Ito, and Akira Kazaoka from the Graduate School of Medical and Pharmaceutical Sciences, Chiba University, conducted an in-depth study on the link between HLA and drug eruptions. Their findings were published in PNAS Nexus.

The researchers first conducted a series of experiments on mice keratinocytes. These keratinocytes, the most common type of skin cell, were engineered to express a specific variant of the HLA gene called HLA-B*57:01, which specifically bind to the antiviral drug abacavir. Then, they validated these findings in genetically modified mice expressing HLA-B*57:01, that were exposed to abacavir.

The researchers found that HLA-B*57:01-expressing keratinocytes that were exposed to abacavir exhibited endoplasmic reticulum (ER) stress responses, such as immediate release of calcium into the cytosol and elevated expression of heat shock protein 70 (HSP70). They also observed an increased production of cytokines and immune cell migration. Abacavir exposure triggered HLA misfolding in the ER, leading to ER stress. Moreover, the researchers observed that the ER stress could be reduced by using 4-phenylbutyrate (4-PB). By alleviating this stress, they managed to suppress the onset of severe drug eruption symptoms. This newfound knowledge could form the basis for innovative treatment options for management of drug eruptions.

HLAs – secondary players for the immune system

But how does this new information contrast with what was already known about HLA? “HLA molecules are an integral component of our immune system, that typically present foreign antigens to white blood cells, which judge these antigens as self or non-self. In this established role, HLAs are usually secondary players,” explains Dr Aoki. “However, our research highlights a novel function of the HLA molecule within skin cells. We revealed that a specific HLA genotype in keratinocytes can recognise certain drugs as foreign, triggering an endoplasmic reticulum stress response.”

Taken together, the findings of this study uncover a new role of HLA proteins in sensing and responding to potential threats in skin cells. Thus, their functions may extend well beyond mere antigen presentation for the immune system. Moreover, considering that the variant of HLA possessed by an individual can be determined through genetic testing, this study could help develop preventive measures and diagnostics against severe adverse drug reactions.

According to Dr Aoki, this is in line with current research directions and trends in medical science.

“In 10 years, we anticipate entering the ‘whole genome era,’ where personalised medicine based on individual genomes will become a standard practice,” he comments. He further adds, “Building on the findings of this study, we believe that a comprehensive understanding of the mechanism underlying HLA-dependent adverse drug reactions will enable the delivery of safe medical care, allowing patients to avoid unnecessary suffering due to side effects.”

Future research might minimise the occurrence of drug eruptions and save people from potentially fatal adverse drug reactions.

Source: Chiba University

Categories : Diseases, Syndromes and ConditionsTags : Leave a comment

Keratinocytes Play a Role in Stable Vitiligo Disease

On By ModernMedia
Targeting keratinocyte metabolism could be a new method of vitiligo treatment. Photo by Hanen BOUBAHRI on Unsplash

A new study published today in JCI Insight reveals the unique cell-to-cell communication networks that can perpetuate inflammation and prevent repigmentation in patients with stable vitiligo disease, and the particular role that keratinocytes play.

“In this study, we couple advanced imaging with transcriptomics and bioinformatics to discover the cell-to-cell communication networks between keratinocytes, immune cells and melanocytes that drive inflammation and prevent repigmentation caused by vitiligo,” said Anand K. Ganesan, MD, PhD, professor at University of California, Irvine. “This discovery will enable us to determine why white patches continue to persist in stable vitiligo disease, which could lead to new therapeutics to treat this disease.”

Vitiligo is an autoimmune skin disease characterised by the progressive destruction of melanocytes by immune cells called autoreactive CD8+ T cells, resulting in disfiguring patches of white depigmented skin. This disease has shown to cause significant psychological distress among patients. Melanocyte destruction in active vitiligo is mediated by CD8+ T cells, but until now, why the white patches in stable disease persist was poorly understood.

“Until now, the interaction between immune cells, melanocytes, and keratinocytes in situ in human skin has been difficult to study due to the lack of proper tools,” said Jessica Shiu, MD, PhD, assistant professor of dermatology and one of the first authors of the study. “By combining non-invasive multiphoton microscopy (MPM) imaging and single-cell RNA sequencing (scRNA-seq), we identified distinct subpopulations of keratinocytes in lesional skin of stable vitiligo patients along with the changes in cellular compositions in stable vitiligo skin that drive disease persistence. In patients that responded to punch grafting treatment, these changes were reversed, highlighting their role in disease persistence.”

MPM is a unique tool that has broad applications in human skin. MPM is a noninvasive imaging technique capable of providing images with sub-micron resolution and label-free molecular contrast which can be used to characterise keratinocyte metabolism in human skin.

Most studies on vitiligo have focused on active disease, while stable vitiligo remains somewhat of a mystery. Studies are currently investigating when metabolically altered keratinocytes first appear and how they may affect the repigmentation process in patients undergoing treatment.

The study findings suggest the possibility of targeting keratinocyte metabolism in vitiligo treatment. Further studies are needed to improve the understanding of how keratinocyte states affect the tissue microenvironment and contribute to disease pathogenesis.

Source: University of California – Irvine