scholarly journals Long-term Hematopoietic Stem Cells as Sanctuary Niche during Treatment Failure in Visceral Leishmaniasis

2021 ◽  
Author(s):  
Laura Dirkx ◽  
Sarah Hendrickx ◽  
Louis Maes ◽  
Guy Caljon
Keyword(s):  
Stem Cells ◽  
Visceral Leishmaniasis ◽  
Treatment Failure ◽  
Hematopoietic Stem Cells ◽  
Cellular Level ◽  
Current Field ◽  
Hematopoietic Stem ◽  
Field Situation ◽  
Relapse Rates

Abstract The increasing frequency of treatment failure in visceral leishmaniasis (VL) has already resulted in discontinuation of various first-line drugs. Although most studies focus on associations with parasitic drug resistance, a knowledge gap remains about other factors determining cure versus relapse. The present study used double bioluminescent/fluorescent Leishmania infantum and L. donovani reporter lines to study relapse at the tissue and cellular level. In combination with 123 different treatments in golden Syrian hamsters, the observations provide evidence of parasites surviving in the bone marrow (BM), identifying this tissue as a sanctuary site from where the host can be recolonized. Long-term hematopoietic stem cells (LT-HSC; Lin- Sca1 + cKit + CD48- CD150+) were found to become readily infected through invasion rather than phagocytosis. Compared to other BM cells and macrophages, LT-HSCs constitute a hospitable cellular niche with low nitric oxide and reactive oxygen species levels and harbouring enormous parasite burdens. Moreover, we found that infected LT-HSCs are less sensitive to antileishmanial reference drugs in comparison to macrophages. Given the important clinical implications for the current field situation of increasing post-treatment relapse rates, this study represents an essential step by identifying the BM cellular niches responsible for Leishmania persistence and treatment failure.

Strategies to Protect Hematopoietic Stem Cells from Culture-Induced Stress Conditions

2020 ◽  
Vol 15 ◽  
Author(s):  
Fatima Aerts-Kaya
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Ex Vivo ◽  
Stress Conditions ◽  
Stress Factors ◽  
Hematopoietic Stem ◽  
Induced Stress

: In contrast to their almost unlimited potential for expansion in vivo and despite years of dedicated research and optimization of expansion protocols, the expansion of Hematopoietic Stem Cells (HSCs) in vitro remains remarkably limited. Increased understanding of the mechanisms that are involved in maintenance, expansion and differentiation of HSCs will enable the development of better protocols for expansion of HSCs. This will allow procurement of HSCs with long-term engraftment potential and a better understanding of the effects of the external influences in and on the hematopoietic niche that may affect HSC function. During collection and culture of HSCs, the cells are exposed to suboptimal conditions that may induce different levels of stress and ultimately affect their self-renewal, differentiation and long-term engraftment potential. Some of these stress factors include normoxia, oxidative stress, extra-physiologic oxygen shock/stress (EPHOSS), endoplasmic reticulum (ER) stress, replicative stress, and stress related to DNA damage. Coping with these stress factors may help reduce the negative effects of cell culture on HSC potential, provide a better understanding of the true impact of certain treatments in the absence of confounding stress factors. This may facilitate the development of better ex vivo expansion protocols of HSCs with long-term engraftment potential without induction of stem cell exhaustion by cellular senescence or loss of cell viability. This review summarizes some of available strategies that may be used to protect HSCs from culture-induced stress conditions.

scholarly journals Leptin receptor, a surface marker for a subset of highly engrafting long-term functional hematopoietic stem cells

Leukemia ◽  
2020 ◽  
Author(s):  
Thao Trinh ◽  
James Ropa ◽  
Arafat Aljoufi ◽  
Scott Cooper ◽  
Anthony Sinn ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Leptin Receptor ◽  
Surface Marker ◽  
Hematopoietic Stem

scholarly journals Long-term repopulating hematopoietic stem cells and “side population” in human steady state peripheral blood

2013 ◽  
Vol 11 (1) ◽  
pp. 625-633 ◽  
Author(s):  
Philippe Brunet de la Grange ◽  
Marija Vlaski ◽  
Pascale Duchez ◽  
Jean Chevaleyre ◽  
Veronique Lapostolle ◽  
...  
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Side Population ◽  
Hematopoietic Stem

scholarly journals Maintenance of Hematopoietic Stem Cells Through Regulation of Wnt and mTOR Pathways.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2309-2309
Author(s):  
Jian Huang ◽  
Peter S. Klein
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Signaling Pathways ◽  
Glycogen Synthase ◽  
Dependent Manner ◽  
Mtor Inhibition ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Abstract 2309 Hematopoietic stem cells (HSCs) maintain the ability to self-renew and to differentiate into all lineages of the blood. The signaling pathways regulating hematopoietic stem cell (HSCs) self-renewal and differentiation are not well understood. We are very interested in understanding the roles of glycogen synthase kinase-3 (Gsk3) and the signaling pathways regulated by Gsk3 in HSCs. In our previous study (Journal of Clinical Investigation, December 2009) using loss of function approaches (inhibitors, RNAi, and knockout) in mice, we found that Gsk3 plays a pivotal role in controlling the decision between self-renewal and differentiation of HSCs. Disruption of Gsk3 in bone marrow transiently expands HSCs in a b-catenin dependent manner, consistent with a role for Wnt signaling. However, in long-term repopulation assays, disruption of Gsk3 progressively depletes HSCs through activation of mTOR. This long-term HSC depletion is prevented by mTOR inhibition and exacerbated by b-catenin knockout. Thus GSK3 regulates both Wnt and mTOR signaling in HSCs, with opposing effects on HSC self-renewal such that inhibition of Gsk3 in the presence of rapamycin expands the HSC pool in vivo. In the current study, we found that suppression of the mammalian target of rapamycin (mTOR) pathway, an established nutrient sensor, combined with activation of canonical Wnt/ß-catenin signaling, allows the ex vivo maintenance of human and mouse long-term HSCs under cytokine-free conditions. We also show that combining two clinically approved medications that activate Wnt/ß-catenin signaling and inhibit mTOR increases the number of long-term HSCs in vivo. Disclosures: No relevant conflicts of interest to declare.

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