- Author
-
F. Aglialoro
- Title
- The bright and DARC side of detection
- Subtitle
- Role of membrane proteins during erythroid maturation
- Supervisors
-
M.M. von Lindern
- Co-supervisors
-
E. van den Akker
- Award date
- 6 November 2020
- Number of pages
- 203
- ISBN
- 9789464190151
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
This thesis aims at elucidating the role of specific membrane proteins crucial during erythroid maturation, niche interactions and erythrocyte functionality. Such knowledge is essential to develop novel therapeutics that regulate erythropoiesis but also to produce cultured erythrocytes for transfusion purposes. In bioreactors as well as within tissue, erythroid cells experience shear stress. We investigated the effects of the mechanosensing cation channel PIEZO1 activation in response to shear stress. PIEZO1 activation activated specific signaling pathways that regulate erythroblasts proliferation and differentiation. In addition PIEZO1-mediated cation influx in erythroblasts also regulates inside-out activation of integrins. Integrins mediate interactions of erythroblasts with the macrophages within the erythroblastic island, thus regulating erythroblast niche interactions. Moreover, we showed that another membrane protein, DARC, mediates interactions between erythroid cells and the bone marrow niche, through binding with SDF-1, the chemokine restricting neutrophil precursors and hematopoietic stem and progenitor cells to the bone marrow. We found that DARC can only bind SDF-1 in immature erythroid cells. Interestingly, Plasmodium vivax uses the membrane protein DARC as the main entry point to invade reticulocytes but not erythrocytes. We found that P.vivax tropism towards in vivo reticulocytes was due to differential DARC epitope exposure. We used this knowledge to optimize an in vitro P.vivax invasion model using in vitro cultured reticulocytes. In conclusion, we showed how expression and signaling of different erythroid membrane proteins have high influence not only on the maturation of the erythroid cell per se but also on the homeostasis of the surrounding environment and pathology.
- Persistent Identifier
- https://hdl.handle.net/11245.1/f36611ac-09d1-4248-af55-f9b7ee59d6b5
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: General introduction
Chapter 2: Mechanical stress mediated Ca²⁺ induced signal transduction in erythroblasts modulates erythropoiesis
Chapter 3: Inside out integrin activation mediated by PIEZO1 signaling in erythroblasts
Chapter 4: DARC extracellular domain remodeling in maturating reticulocytes explains Plasmodium vivax tropism
Chapter 5: Towards long term continuous Plasmodium vivax blood stage cultures using in vitro cultured reticulocytes
Chapter 6: Differential interaction between DARC and SDF-1 on erythrocytes and their precursors
Chapter 7: General discussion
EN summary; NL samenvatting; IT sommario; List of publications; PhD portfolio; Curriculum vitae; Acknowledgements
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