Novel Insights into Haematopoietic Stem Cell Regulation and Function
Author
Summary, in English
HSCs reside in the bone marrow and the fate of each HSC is tightly regulated by both intrinsic and extrinsic factors. The studies presented in this thesis have identified novel intrinsic regulatory factors for haematopoietic stem cell self-renewal and quiescence. In summary, our results demonstrate the importance of preserved SLFN2 and BMP signalling for proper HSC functionality. We show that loss of SLFN2 function in HSCs causes a defect in reconstitution potential of the HSCs by perturbing cell cycle status and stress response (Paper I). SLFN2 is known to regulate cell quiescence and apoptosis in other cell types and our data now shows that it plays a similar role in HSCs. Furthermore, we show that loss of BMP signalling also leads to a defect in HSC reconstitution potential, in part mediated via TJP1 (Paper II), which is a previously known regulator of self-renewal in other stem cells. Our study thus establishes a previously unknown role for BMP signalling in adult HSCs and demonstrates a putative connection between BMP and TJP1 in HSCs.
HSC transplantation is today the only curative treatment for many haematopoietic disorders, but it is associated with many risks for the patients. Prior to HSC transplantation patients today undergo extensive conditioning, often involving irradiation or chemotherapy, which are independently associated with increased morbidity and mortality. As haematopoietic disorders often originate from the HSC itself, the HSCs are in many respects less fit than HSCs in a healthy individual. The work in this thesis also shows, using a mouse model of Diamond-Blackfan anaemia, that HSC transplantation can be successful even without conditioning or with a reduced conditioning regimen (Paper III), i.e. that the less fit HSCs can be out-competed by healthy HSCs.
Taken together, we have identified novel factors that affect HSC function and fate options and provided insight into HSC transplantation in haematopoietic disorders.
Department/s
Publishing year
2022
Language
English
Full text
- Available as PDF - 16 MB
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Document type
Dissertation
Publisher
Lund University, Faculty of Medicine
Topic
- Cell and Molecular Biology
- Hematology
Keywords
- Haematopoiesis
- Haematopoietic stem cell
- Stem cell regulation
- Haematopoietic stem cell transplantation
Status
Published
Research group
- Hematopoiesis and Gene Therapy
ISBN/ISSN/Other
- ISBN: 978-91-8021-288-5
Defence date
4 October 2022
Defence time
13:00
Defence place
Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/63344883917
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