Interplay between chondrocytes and mesenchymal stem cells via Fas/FasL pathway.
Mesenchymal stem cells (MSCs) are referred to as conductors of tissue repair and regeneration by secreting trophic mediators. Previous studies have shown that in co-cultures of primary chondrocytes and MSCs, the MSCs disappear over time while simultaneously having a beneficial effect on cartilage formation both in vitro and in vivo1-3. The underlying mechanisms haven’t fully studied yet. Researchers assumed that the ratio of MSCs decreased dramatically maybe due to massive cell death of MSCs by apoptosis1. Indeed, previous work also showed that the interactions between chondrocytes and macrophages may induce the membrane protein FasL on chondrocytes, which in turn induce the apoptosis of macrophages and suppress tissue reactions, promoting the maturation of tissue-engineered cartilage4. This data indicates a role of the Fas/FasL pathway in the interaction between chondrocytes and MSCs.
Fas, also called APO-1 or CD95, is a type I membrane protein in the tumor necrosis factor (TNF)/nerve growth factor receptor family5, and Fas ligand is a type II membrane protein that belongs to the TNF family of cytokines6,7. Activation of the Fas receptor in Fas-expressing cells in response to agonistic antibodies or ligand binding triggers apoptosis8. So in this project we will examine the Fas/FasL pathway status in different chondrocytes and MSCs co-culture systems.
In tissue regeneration studies, cell death was considered as a consequence of injury, lack of oxygen and not as a regenerative factor, until recently. Researchers proposed the concept of “altruistic cell suicide” based on their observation that dying cells could induce proliferation in their neighboring cells9. During apoptosis, apoptotic bodies containing biological information are transferred from apoptotic to non-apoptotic cells10. This data indicates that the apoptotic bodies likely play an important role in the paracrine signaling supporting tissue repair and regeneration. Thus the disappearance over time of MSCs from the injured tissue could reflect the death of MSCs but at present other explanations cannot be excluded. The extent to which MSC’s cell death contributes to tissue regeneration as well as the underlying mechanism of this “altruistic cell death” deserves further study.
Apoptotic body is one type of microvesicles. Cell communication by means of microvesicles is considered to be a universal way for cells to interact with each other and influence the behavior of other neighboring cells by exchanging material and information. Studies indicated that hypoxia environment can promote the release of microvesicles from MSC11, and enhance in vitro proliferation of chondrocytes12. In this project, we will also focus on the influence of hypoxia environment on the Fas/FasL pathway status and on the interaction between chondrocytes and MSCs in different co-culture systems.
Daily supervisor: Yao Fu, MSc
Supervisor: Dr.ing. Sanne Both
If you are interested in this assignment, please contact: Dr. Janneke Alers, contact person for all DBE assignments
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2. Wu L., Prins H.-J., Helder M. N., van Blitterswijk C. A., Karperien M. Trophic effects of mesenchymal stem cells in chondrocyte co-cultures are independent of culture conditions and cell sources. Tissue Eng Part A 18, 1542, 2012.
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11. Bian S, Zhang L, Duan L, et al. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl) 92, 387-397, 2014.
12. Leijten, J., et al., Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate. Proc Natl Acad Sci U S A 111, 13954, 2014.