In vitro blood production from induced pluripotent stem cellsPhD thesis defense Marten Hansen News
Marten Hansen set up a system to culture blood cells from induced pluripotent stem cells. His results reveal insights into the development of platelets from stem cells derived from healthy individuals as well as patients with platelet disease. His model takes important steps towards novel therapies and transfusion products and allows to asses the effects of drugs on the hematopoietic system. He will defend his PhD thesis on 25 November 2020.
The aim of this thesis was to establish a cell system that could faithfully recapitulate hematopoietic development from induced pluripotent stem cells (iPSC), and specifically the development of the megakaryopoietic lineage. To this end we developed novel methodology to generate and differentiate iPSC to hematopoietic/megakaryocyte lineages.
We showed that megakaryoblasts can be reprogrammed into iPSC lines with similar pluripotent characteristics as other non-megakaryoid derived iPSC lines, thus potentially preserving persisting epigenetic footprints that may be crucial for hematopoietic differentiation.
We developed an efficient hematopoietic differentiation system allowing molecular characterization of defects in megakaryopoiesis and in hereditary thrombopenia but also drug screening. In this thesis we used patient specific BDPLT17 iPSC lines, which recapitulated the phenotypes of this grey platelet like syndrome, and enabled us to uncover (part of) the molecular mechanisms underlying BDPLT17. Specifically, the DNA binding defective mutated GFI1B recruits chromatin remodeling protein LSD1 thereby inhibiting the normal function of GFI1B in a dominant negative manner.
The data also explains thrombopenia induced by LSD1 inhibitors used to treat solid tumors, underscoring the usability of iPSC models to monitor drug sensitivity. In addition, we demonstrated an essential role of LSD1/GFI1B during hemogenic endothelium transition to hematopoietic stem and progenitor cells from iPSC.
The data indicate that patient derived, and wild type iPSC models can be investigated using the novel developed methodology. The results from this thesis further our mechanistic understanding of megakaryopoietic pathology and may allow the production of hematopoietic cells including platelets from iPSC, thus taking important steps towards novel therapies and transfusion products.
- Promotor MM von Lindern PhD
- Copromotores E van den Akker PhD and BA van der Reijden PhD
- Venue Agnietenkapel and online