Alexander Nyström's Lab

About the lab

Featured research (47)

The size and relatively high GC content of cDNAs are challenges for efficient targeted engineering of large collagens. There are both basic biological and therapeutic interests in the ability to modify collagens, as this would allow for studies precisely describing interactions of collagens with specific interaction partners, addressing consequences of individual disease-causing mutations, and assessing therapeutic applicability of precision medicine approaches. Using collagen VII as an example, we will here describe a strategy for rapid and simple modification of cDNAs encoding large collagens. The method is flexible and can be used for the creation of point mutations, small or large deletions, and insertion of DNA.
Loss-of-function mutations in the gene encoding type VII collagen underlie recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized by skin and mucosal blistering, impaired wound healing, and diffuse dermal inflammation and fibrosis. Transforming growth factor-β signaling plays a crucial role in determining RDEB fibrotic microenvironment that leads to the development of disabling secondary disease manifestations, including hand and foot deformities. Experimental findings indicate that expression levels of decorin, a small leucine-rich proteoglycan and an endogenous TGF-β inhibitor, can modulate RDEB disease phenotype by contrasting dermal fibroblast fibrotic behavior. In this study, the ability of decorin to modify RDEB course was investigated by systemically treating RDEB mice with a lentivirus expressing human decorin. Overexpressed decorin was able to enhance survival, and to limit digit contraction and the development of paw deformities. These effects were associated with decreased TGF-β1 levels and TGF-β signaling activation. Fibrotic traits were strongly reduced in paw skin and also attenuated in the non-chronically injured back skin. However, the expression of pro-inflammatory proteins was not decreased in both paw and back skin. Our findings confirm TGF-β role in promoting fibrosis and disease progression in RDEB, and show that decorin counteracts disease manifestations by inhibiting TGF-β activation. More generally, our data indicate that modifying extracellular matrix composition is an option to improve RDEB disease course.
An extracellular matrix (ECM) is a prerequisite for multicellular life. It is adapted to tissues and constantly undergoes changes to preserve microenvironmental homeostasis. The ECM acts as a structural scaffold that establishes tissue architecture and provides tensile strength. It has cell-instructive functions by serving as a reservoir and presenter of soluble agents, being directly signaling, integrating transmission of mechanical and biological cues, or serving as a co-factor potentiating signaling. The skin contains a highly developed, mechanically tough, but yet flexible ECM. The tissue-specific features of this ECM are largely attributed by minor ECM components. A large number of genetic and acquired ECM diseases with skin manifestations, provide an illustrative testament to the importance of correct assembly of the ECM for dermal homeostasis. Here, we will present the composition and features of the skin ECM during homeostasis and regeneration. We will discuss genetic and acquired ECM diseases affecting skin, and provide a short outlook to therapeutic strategies for them.
Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous skin fragility disorder characterized by trauma-induced skin dissociation and the development of painful wounds. So far, mutations in 20 genes have been described as being associated with more than 30 clinical EB subtypes. The era of whole-exome sequencing has revolutionized EB diagnostics with gene panels being developed in several EB centers and allowing quicker diagnosis and prognostication. With the advances of gene editing, more focus has been placed on gene editing-based therapies for targeted treatment. However, their implementation in daily care will still take time. Thus, a significant focus is currently being placed on achieving a better understanding of the pathogenetic mechanisms of each subtype and using this knowledge for the design of symptom-relief therapies, i.e. treatment options aimed at ameliorating and not curing the disease.

Lab head

Alexander Nyström
  • Dermatology

Members (6)

Eijiro Akasaka
  • Hirosaki University
Christine Gretzmeier
  • University Medical Center Freiburg
Olivier Bornert
  • University Medical Center Freiburg
Pauline Nauroy
  • University of Freiburg
Daniel Kruppa
  • University Medical Center Freiburg

Alumni (2)

Tobias Kühl
  • University Hospital Essen
Agnès Tessier
  • Dow Chemical Company