scholarly journals Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

2018 ◽  
Vol 245 (2) ◽  
pp. 138-146 ◽  
Author(s):  
Hélène FE Gleitz ◽  
Rafael Kramann ◽  
Rebekka K Schneider
Keyword(s):  
Molecular Dynamics ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Haematopoietic Stem Cell ◽  
Bone Marrow Fibrosis ◽  
Novel Therapeutics ◽  
Cell Niche ◽  
Marrow Fibrosis

scholarly journals The Haematopoietic Stem Cell Niche: New Insights into the Mechanisms Regulating Haematopoietic Stem Cell Behaviour

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Andrew J. Lilly ◽  
William E. Johnson ◽  
Christopher M. Bunce
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Cell Types ◽  
Haematopoietic Stem Cell ◽  
Cell Behaviour ◽  
Ongoing Research ◽  
Hsc Niche ◽  
Numerous Cell ◽  
Cell Niche

The concept of the haematopoietic stem cell (HSC) niche was formulated by Schofield in the 1970s, as a region within the bone marrow containing functional cell types that can maintain HSC potency throughout life. Since then, ongoing research has identified numerous cell types and a plethora of signals that not only maintain HSCs, but also dictate their behaviour with respect to homeostatic requirements and exogenous stresses. It has been proposed that there are endosteal and vascular niches within the bone marrow, which are thought to regulate different HSC populations. However, recent data depicts a more complicated picture, with functional crosstalk between cells in these two regions. In this review, recent research into the endosteal/vascular cell types and signals regulating HSC behaviour are considered, together with the possibility of a single subcompartmentalised niche.

scholarly journals Tug of war in the haematopoietic stem cell niche: do myeloma plasma cells compete for the HSC niche?

2012 ◽  
Vol 2 (9) ◽  
pp. e91-e91 ◽  
Author(s):  
J E Noll ◽  
S A Williams ◽  
L E Purton ◽  
A C W Zannettino
Keyword(s):  
Stem Cell ◽  
Stem Cell Niche ◽  
Plasma Cells ◽  
Haematopoietic Stem Cell ◽  
Hsc Niche ◽  
Cell Niche

scholarly journals Closer to Nature: The Role of MSCs in Recreating the Microenvironment of the Hematopoietic Stem Cell Niche in vitro

2022 ◽  
pp. 1-10
Author(s):  
Patrick Wuchter ◽  
Anke Diehlmann ◽  
Harald Klüter
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Model Systems ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche

<b><i>Background:</i></b> The stem cell niche in human bone marrow provides scaffolds, cellular frameworks and essential soluble cues to support the stemness of hematopoietic stem and progenitor cells (HSPCs). To decipher this complex structure and the corresponding cellular interactions, a number of in vitro model systems have been developed. The cellular microenvironment is of key importance, and mesenchymal stromal cells (MSCs) represent one of the major cellular determinants of the niche. Regulation of the self-renewal and differentiation of HSPCs requires not only direct cellular contact and adhesion molecules, but also various cytokines and chemokines. The C-X-C chemokine receptor type 4/stromal cell-derived factor 1 axis plays a pivotal role in stem cell mobilization and homing. As we have learned in recent years, to realistically simulate the physiological in vivo situation, advanced model systems should be based on niche cells arranged in a three-dimensional (3D) structure. By providing a dynamic rather than static setup, microbioreactor systems offer a number of advantages. In addition, the role of low oxygen tension in the niche microenvironment and its impact on hematopoietic stem cells need to be taken into account and are discussed in this review. <b><i>Summary:</i></b> This review focuses on the role of MSCs as a part of the bone marrow niche, the interplay between MSCs and HSPCs and the most important regulatory factors that need to be considered when engineering artificial hematopoietic stem cell niche systems. <b><i>Conclusion:</i></b> Advanced 3D model systems using MSCs as niche cells and applying microbioreactor-based technology are capable of simulating the natural properties of the bone marrow niche more closely than ever before.

scholarly journals Population dynamics of normal and leukaemia stem cells in the haematopoietic stem cell niche show distinct regimes where leukaemia will be controlled

2013 ◽  
Vol 10 (81) ◽  
pp. 20120968 ◽  
Author(s):  
Adam L. MacLean ◽  
Cristina Lo Celso ◽  
Michael P. H. Stumpf
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Immune Cells ◽  
Stem Cell Niche ◽  
Haematopoietic Stem Cell ◽  
Current Analysis ◽  
Oncogenic Potential ◽  
Viable Population ◽  
Cell Niche ◽  
Potential Cancer

Haematopoietic stem cells (HSCs) are responsible for maintaining immune cells, red blood cells and platelets throughout life. HSCs must be located in their ecological niche (the bone marrow) to function correctly, that is, to regenerate themselves and their progeny; the latter eventually exit the bone marrow and enter circulation. We propose that cells with oncogenic potential—cancer/leukaemia stem cells (LSC)—and their progeny will also occupy this niche. Mathematical models, which describe the dynamics of HSCs, LSCs and their progeny allow investigation into the conditions necessary for defeating a malignant invasion of the niche. Two such models are developed and analysed here. To characterize their behaviour, we use an inferential framework that allows us to study regions in parameter space that give rise to desired behaviour together with an assessment of the robustness of the dynamics. Using this approach, we map out conditions under which HSCs can outcompete LSCs. In therapeutic applications, we clearly want to drive haematopoiesis into such regimes and the current analysis provide some guidance as to how we can identify new therapeutic targets. Our results suggest that maintaining a viable population of HSCs and their progenies in the niche may often already be nearly sufficient to eradicate LSCs from the system.

scholarly journals The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis

Blood ◽  
2018 ◽  
Vol 131 (19) ◽  
pp. 2111-2119 ◽  
Author(s):  
Rafael Kramann ◽  
Rebekka K. Schneider
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Gli Proteins ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Organ Fibrosis

Abstract Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis remains obscure. Recent work has demonstrated that Gli1+ and LepR+ mesenchymal stromal cells (MSCs) are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation of Gli1+ MSCs or pharmacologic targeting of hedgehog (Hh)-Gli signaling ameliorated fibrosis in mouse models of myelofibrosis (MF). Moreover, pharmacologic or genetic intervention in platelet-derived growth factor receptor α (Pdgfrα) signaling in Lepr+ stromal cells suppressed their expansion and ameliorated MF. Improved understanding of cellular and molecular mechanisms in the hematopoietic stem cell niche that govern the transition of MSCs to myofibroblasts and myofibroblast expansion in MF has led to new paradigms in the pathogenesis and treatment of MF. Here, we highlight the central role of malignant hematopoietic clone-derived megakaryocytes in reprogramming the hematopoietic stem cell niche in MF with potential detrimental consequences for hematopoietic reconstitution after allogenic stem cell transplantation, so far the only therapeutic approach in MF considered to be curative. We and others have reported that targeting Hh-Gli signaling is a therapeutic strategy in solid organ fibrosis. Data indicate that targeting Gli proteins directly inhibits Gli1+ cell proliferation and myofibroblast differentiation, which results in reduced fibrosis severity and improved organ function. Although canonical Hh inhibition (eg, smoothened [Smo] inhibition) failed to improve pulmonary fibrosis, kidney fibrosis, or MF, the direct inhibition of Gli proteins ameliorated fibrosis. Therefore, targeting Gli proteins directly might be an interesting and novel therapeutic approach in MF.

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