Label retaining haematopoietic stem cells preserve their stemness during Plasmodium berghei infection and maintain low metabolic statuses
File(s)
Author(s)
Georgiou, Christiana
Type
Thesis
Abstract
Blood production is attributed to a rare haematopoietic population of cells called haematopoietic stem cells (HSCs). HSCs reside in specialised BM microenvironments, that secrete factors essential for HSC maintenance, quiescence, and survival. In health, HSCs occasionally proliferate to self-renew or differentiate, however during severe infection they are forced out of quiescence and into the cell cycle to replenish downstream haematopoieteic cells consumed during the immune response. Studies showed that due to proliferation-induced stress, the few HSCs that remain become deprived of their functional properties. However, in my opinion, it’s impossible for an organism to lose almost completely its functional HSCs. Using the rodent malaria parasite P. berghei, I study HSCs’ heterogeneous responses by identifying HSC subsets based on the NHS-ester-Biotin labelling system. A short pulse-chase during infection development allowed the identification of cells with limited, BiotinHi, or faster, BiotinLo, proliferation kinetics in both SLAM CD48neg and E-SLAM HSC compartments. Chronic EdU administration confirmed that DNA replication correlated with biotin dilution. When functional properties of E-SLAM -Biotin subsets in both control and infected animals were studied, I found that E-SLAM BiotinHi HSCs purified from infected animals were highly functional, leading to engraftment similar to that of HSCs purified from healthy controls. In contrast, BiotinLo HSCs engrafted poorly. This was evident in the transcriptional profiles of BiotinHi “infected” and control HSCs, which carried molecular signatures associated with stemness, unlike that of BiotinLo HSCs from infected animals. Furthermore, I show that BiotinHi maintained low reactive oxygen species (ROS), mitochondria membrane potential (MMP) and mitochondrial mass compared to BiotinLo HSCs purified from infected animals. Relevant to understanding possible niche-dependent regulation of BiotinHi HSCs I investigated their localisation as well as infection-induced changes in the bone marrow microenvironment. In conclusion, I identified a “reserve” pool of HSCs that maintain stemness even after strong infection.
Version
Open Access
Date Issued
2023-12-15
Date Awarded
2024-04-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Lo Celso, Cristina
Cunha Luis, Tiago
Sponsor
Welcome Trust (London, England)
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)