| 11. |
- Warsi, Sarah
(författare)
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Novel Insights into Haematopoietic Stem Cell Regulation and Function
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The haematopoietic stem cell (HSC) is a somatic stem cell essential for life long haematopoiesis; HSCs have the capability to differentiate into all mature types of blood cells and can also undergo self-renewal to maintain their own numbers. They also have the potential to reconstitute a complete haematopoietic system following HSC transplantation, also known as bone marrow transplantation, which is used to treat many haematopoietic disorders. To obtain successful long-term engraftment of HSCs, a large number of cells need to be transplanted. This limiting factor in the clinical use of HSC transplantation could be overcome by methods that expand and maintain HSCs ex vivo. Despite continuous progress in this field, efficient HSC expansion has had limited success in part due to limited knowledge on HSC regulation. Better understanding of how HSC fate options are governed in the HSCs’ natural environment can contribute to the development of future expansion protocols and improved HSC therapies. 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.
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| 12. |
- Warsi, Sarah, et al.
(författare)
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Schlafen2 is a regulator of quiescence in adult murine hematopoietic stem cells
- 2022
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 107:12, s. 2884-2896
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Tidskriftsartikel (refereegranskat)abstract
- Even though hematopoietic stem cells (HSC) are characterized by their ability to self-renew and differentiate, they primarily reside in quiescence. Despite the immense importance of this quiescent state, its maintenance and regulation is still incompletely understood. Schlafen2 (Slfn2) is a cytoplasmic protein known to be involved in cell proliferation, differentiation, quiescence, interferon response, and regulation of the immune system. Interestingly, Slfn2 is highly expressed in primitive hematopoietic cells. In order to investigate the role of Slfn2 in the regulation of HSC we have studied HSC function in the elektra mouse model, where the elektra allele of the Slfn2 gene contains a point mutation causing loss of function of the Slfn2 protein. We found that homozygosity for the elektra allele caused a decrease of primitive hematopoietic compartments in murine bone marrow. We further found that transplantation of elektra bone marrow and purified HSC resulted in a significantly reduced regenerative capacity of HSC in competitive transplantation settings. Importantly, we found that a significantly higher fraction of elektra HSC (as compared to wild-type HSC) were actively cycling, suggesting that the mutation in Slfn2 increases HSC proliferation. This additionally caused an increased amount of apoptotic stem and progenitor cells. Taken together, our findings demonstrate that dysregulation of Slfn2 results in a functional deficiency of primitive hematopoietic cells, which is particularly reflected by a drastically impaired ability to reconstitute the hematopoietic system following transplantation and an increase in HSC proliferation. This study thus identifies Slfn2 as a novel and critical regulator of adult HSC and HSC quiescence.
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