Plasmacytoid dendritic cells contribute to the spatio-temporal distribution of megakaryocytes in the bone marrow

Weitz, Jutta (2024): Plasmacytoid dendritic cells contribute to the spatio-temporal distribution of megakaryocytes in the bone marrow. Dissertation, LMU München: Faculty of Medicine

Abstract

Megakaryopoiesis describes the maturation from haematopoietic stem cells (HSCs) to megakaryocytes (MKs). Megakaryocytes are large and scarce cells in the bone marrow which produce platelets. The production of platelets is achieved by fragmentation of the MK cytoplasm, which ultimately leads to MK apoptosis. Multiple studies have studied megakaryopoiesis, all trying to elucidate responsible factors for the differentiation and maturation of HSCs. This works aims to investigate the role of plasmacytoid dendritic cells (pDCs) in the regulation of megakaryopoiesis. Cell quantification of pDCs, megakaryocytes and megakaryocyte progenitors (MKPs) in the bone marrow was performed by confocal microscopy and fluorescence-activated cell sorting (FACS). Confocal microscopy was also used to characterize the cell-to-cell interactions between pDCs and MKs or MKPs, as well as the spatial distribution of these cells in the bone marrow. We observed a high number of pDC-MK interactions in the bone marrow of untreated mice. Next, pDCs were ablated in genetically modified mice, pDC-DTR, using the diphtheria toxin. Here, the number of MKs and MKPs significantly decreased after 3 days of pDC depletion. In addition, the recruitment of MKs and MKPs towards the vasculature – which is necessary for platelet production – was impaired and the remaining population of MKs showed an increased ploidy, suggesting that they were older than the MKs in steady state. Together, these results indicate that pDCs may influence the maturation and migration of MKs and MKPs towards the vascular niche. We hypothesize that pDCs can sense the apoptotic MKs at the end of their plateletproducing life and induce MKP proliferation in order to replace the dying MKs. Since pDCs are the major producer of interferon α (IFNα), treatment with IFNα was used to investigate its possible role in the signaling between pDCs and MKPs. In our experiment, this treatment showed no effect on the number and the distribution of MKs and MKPs in our experiment. However, due to the limitations os our setup, the role of IFNα in megakaryopoiesis remains to be clarified.

• Item Type: Theses (Dissertation, LMU Munich)
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 14. November 2024
• 1. Referee: Schulz, Christian
• Signature of the printed copy: 0700/UMD 22217