| 1. |
- Karlsson, Christine, et al.
(författare)
-
RNA interference screening to detect targetable molecules in hematopoietic stem cells.
- 2014
-
Ingår i: Current Opinion in Hematology. - 1531-7048. ; 21:4, s. 283-288
-
Forskningsöversikt (refereegranskat)abstract
- The molecular principles regulating hematopoietic stem cells (HSCs) remain incompletely defined. In this review, we will discuss how RNA interference (RNAi) screening has emerged as a new and powerful tool to molecularly dissect various functional aspects of both normal and malignant HSCs, and how this may ultimately enable the discovery of novel therapeutic targets for clinical applications.
|
|
| 2. |
- Knudsen, Kasper Jermiin, et al.
(författare)
-
ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation.
- 2015
-
Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 29:18, s. 1915-1929
-
Tidskriftsartikel (refereegranskat)abstract
- The balance between self-renewal and differentiation is crucial for the maintenance of hematopoietic stem cells (HSCs). Whereas numerous gene regulatory factors have been shown to control HSC self-renewal or drive their differentiation, we have relatively few insights into transcription factors that serve to restrict HSC differentiation. In the present work, we identify ETS (E-twenty-six)-related gene (ERG) as a critical factor protecting HSCs from differentiation. Specifically, loss of Erg accelerates HSC differentiation by >20-fold, thus leading to rapid depletion of immunophenotypic and functional HSCs. Molecularly, we could demonstrate that ERG, in addition to promoting the expression of HSC self-renewal genes, also represses a group of MYC targets, thereby explaining why Erg loss closely mimics Myc overexpression. Consistently, the BET domain inhibitor CPI-203, known to repress Myc expression, confers a partial phenotypic rescue. In summary, ERG plays a critical role in coordinating the balance between self-renewal and differentiation of HSCs.
|
|
| 3. |
- Miharada, Natsumi, et al.
(författare)
-
Uncoupling key determinants of hematopoietic stem cell engraftment through cell-specific and temporally controlled recipient conditioning
- 2021
-
Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 16:7, s. 1705-1717
-
Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic stem cells (HSCs) are typically characterized by transplantation into irradiated hosts in a highly perturbed microenvironment. Here, we show that selective and temporally controlled depletion of resident HSCs through genetic deletion of Gata2 constitutes efficient recipient conditioning for transplantation without irradiation. Strikingly, we achieved robust engraftment of donor HSCs even when delaying Gata2 deletion until 4 weeks after transplantation, allowing homing and early localization to occur in a completely non-perturbed environment. When HSCs from the congenic strains Ly5.1 and Ly5.2 were competitively transplanted, we found that the more proliferative state of Ly5.2 HSCs was associated with superior long-term engraftment when using conditioning by standard irradiation, while higher CXCR4 expression and a better homing ability of Ly5.1 HSCs strongly favored the outcome in our inducible HSC depletion model. Thus, the mode and timing of recipient conditioning challenges distinct functional features of transplanted HSCs.
|
|
| 4. |
- Rak, Justyna, et al.
(författare)
-
Cytohesin 1 regulates homing and engraftment of human hematopoietic stem and progenitor cells
- 2017
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 129:8, s. 950-958
-
Tidskriftsartikel (refereegranskat)abstract
- Adhesion is a key component of hematopoietic stem cell regulation mediating homing and retention to the niche in the bone marrow. Here, using an RNA interference screen, we identify cytohesin 1 (CYTH1) as a critical mediator of adhesive properties in primary human cord blood-derived hematopoietic stem and progenitor cells (HSPCs). Knockdown of CYTH1 disrupted adhesion of HSPCs to primary human mesenchymal stroma cells. Attachment to fibronectin and ICAM1, 2 integrin ligands, was severely impaired, and CYTH1-deficient cells showed a reduced integrin b1 activation response, suggesting that CYTH1 mediates integrin-dependent functions. Transplantation of CYTH1-knockdown cells to immunodeficient mice resulted in significantly lower long-term engraftment levels, associated with a reduced capacity of the transplanted cells to home to the bone marrow. Intravital microscopy showed that CYTH1 deficiency profoundly affects HSPC mobility and localization within the marrow space and thereby impairs proper lodgment into the niche. Thus, CYTH1 is a novel major regulator of adhesion and engraftment in human HSPCs through mechanisms that, at least in part, involve the activation of integrins.
|
|
| 5. |
- Safaee Talkhoncheh, Mehrnaz, et al.
(författare)
-
Ciclopirox Ethanolamine Preserves the Immature State of Human HSCs by Mediating Intracellular Iron Content
- 2023
-
Ingår i: Blood Advances. - 2473-9529. ; 7:24, s. 7407-7417
-
Tidskriftsartikel (refereegranskat)abstract
- Culture conditions in which hematopoietic stem cells (HSCs) can be expanded for clinical benefit are highly sought after. To elucidate regulatory mechanisms governing the maintenance and propagation of human HSCs ex vivo, we screened libraries of annotated small molecules in human cord blood (CB) cells using an optimized assay for detection of functional HSCs during culture. We found that the antifungal agent ciclopirox ethanolamine (CPX) selectively supported immature CD34+CD90+ cells during culture and enhanced their long-term in vivo repopulation capacity. Purified HSCs treated with CPX showed a reduced cell division rate and an enrichment of HSC- specific gene expression patterns. Mechanistically, we found that the HSC stimulating effect of CPX was directly mediated by chelation of the intracellular iron pool, which in turn affected iron-dependent proteins and enzymes mediating cellular metabolism and respiration. Our findings unveil a significant impact of iron homeostasis in regulation of human HSCs, with important implications for both basic HSC biology and clinical hematology.
|
|
