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 Hemmule: A Novel Structure with the Properties of the Stem Cell Niche

2020 ◽  
Vol 21 (2) ◽  
pp. 539
Author(s):  
Vitaly Vodyanoy ◽  
Oleg Pustovyy ◽  
Ludmila Globa ◽  
Randy J. Kulesza ◽  
Iryna Sorokulova
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Novel Structure ◽  
Hematopoietic Stem Cell Niches ◽  
Cell Niche ◽  
Stem Cell Niches ◽  
Rat Bone

Stem cells are nurtured and regulated by a specialized microenvironment known as stem cell niche. While the functions of the niches are well defined, their structure and location remain unclear. We have identified, in rat bone marrow, the seat of hematopoietic stem cells—extensively vascularized node-like compartments that fit the requirements for stem cell niche and that we called hemmules. Hemmules are round or oval structures of about one millimeter in diameter that are surrounded by a fine capsule, have afferent and efferent vessels, are filled with the extracellular matrix and mesenchymal, hematopoietic, endothelial stem cells, and contain cells of the megakaryocyte family, which are known for homeostatic quiescence and contribution to the bone marrow environment. We propose that hemmules are the long sought hematopoietic stem cell niches and that they are prototypical of stem cell niches in other organs.

Ectopic Human Mesenchymal Stem Cell-Coated Scaffolds Create An In Vivo Leukemia Niche in NOD/SCID Mice.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 559-559
Author(s):  
Sarah Rivkah Vaiselbuh ◽  
Morris Edelman ◽  
Jeffrey Michael Lipton ◽  
Johnson M. Liu
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Scid Mice ◽  
Cxcr4 Antagonist ◽  
Cell Niche

Abstract Abstract 559 Introduction: Different cellular components of the normal hematopoietic niche have been identified. However, the niche for malignant hematopoiesis remains to be elucidated. Recent work of other groups has suggested that hematopoietic stem cells (HSC) within the bone marrow anchor themselves in place by attaching to osteoblasts and/or vascular sinusoid endothelial cells. We have recently identified mesenchymal stem cells (MSC) as niche-maker cells and found a crucial role of the SDF-1/CXCR4 axis in this process. Stromal Derived Factor-1 (SDF-1/CXCL12) regulates stem cell trafficking and the cell cycle via its receptor CXCR4. Methods: Polyurethane scaffolds, coated in vitro with human bone marrow MSC, were implanted subcutaneously in non-irradiated NOD/SCID mice. CD34+ HSC or primary AML cells (from a leukapheresis product) were injected either in situ or retro-orbitally in the mice and analyzed for engraftment. The mice were treated twice per week with in situ injections of SDF-1, AMD3100 (a CXCR4 antagonist) or PBS (control). After 2 to 4 weeks, the scaffolds were processed and evaluated for cell survival in the mesenchymal niche by immunohistochemistry. Results: We created in vitro MSC-coated scaffolds that retained inoculated AML cells in the presence of SDF-1, while AML cells seeded on empty scaffolds were not retained. In vivo in NOD/SCID mice, the MSC-coated scaffolds, in the presence of SDF-1 enabled homing of both in situ injected normal CD34+ HSC and retroorbital- or in situ injected primary human AML cells. The scaffolds were vascularized and showed osteoclasts and adipocytes present, suggestive of an ectopic human bone marrow microenvironment in the murine host. Finally, the SDF-1-treated scaffolds showed proliferation of the MSC stromal layer with multiple adherent AML cells, while in the AMD3100-treated scaffolds the stromal lining was thin and disrupted at several points, leaving AML cells free floating in proximity. The PBS-treated control-scaffold showed a thin single cell MSC stromal layer without disruption, with few AML cells attached. Conclusion: The preliminary data of this functional ectopic human microenvironment in NOD/SCID mice suggest that AMD3100 (a CXCR4 antagonist) can disrupt the stem cell niche by modulation of the mesenchymal stromal. Further studies are needed to define the role of mesenchymal stem cells in maintaining the hematopoietic/leukemic stem cell niche in vivo. In Vivo Leukemia Stem Cell Niche: (A) Empty polyurethane scaffold. (B)Vascularization in SQ implanted MSC-coated scaffold (s) niche in NOD/SCID mice. (C) DAB Peroxidase (brown) human CD45 positive nests of AML cells (arrows) 1 week after direct in situ AML injection. (D) Human CD45 positive myeloid cells adhere to MSC in vivo (arrows). Disclosures: No relevant conflicts of interest to declare.

Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3026-3035 ◽  
Author(s):  
Jean-Jacques Lataillade ◽  
Olivier Pierre-Louis ◽  
Hans Carl Hasselbalch ◽  
Georges Uzan ◽  
Claude Jasmin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Stem Cell Niche ◽  
Primary Myelofibrosis ◽  
Hematopoietic Stem ◽  
Stem Cell Proliferation ◽  
Cell Niche

Abstract Primary myelofibrosis (PMF) is the rarest and the most severe Philadelphia-negative chronic myeloproliferative syndrome. By associating a clonal proliferation and a mobilization of hematopoietic stem cells from bone marrow to spleen with profound alterations of the stroma, PMF is a remarkable model in which deregulation of the stem cell niche is of utmost importance for the disease development. This paper reviews key data suggesting that an imbalance between endosteal and vascular niches participates in the development of clonal stem cell proliferation. Mechanisms by which bone marrow niches are altered with ensuing mobilization and homing of neoplastic hematopoietic stem cells in new or reinitialized niches in the spleen and liver are examined. Differences between signals delivered by both endosteal and vascular niches in the bone marrow and spleen of patients as well as the responsiveness of PMF stem cells to their specific signals are discussed. A proposal for integrating a potential role for the JAK2 mutation in their altered sensitivity is made. A better understanding of the cross talk between stem cells and their niche should imply new therapeutic strategies targeting not only intrinsic defects in stem cell signaling but also regulatory hematopoietic niche–derived signals and, consequently, stem cell proliferation.

scholarly journals Hemmule: A Novel Structure with the Properties of the Stem Cell Niche

2019 ◽  
Author(s):  
Vitaly Vodyanoy ◽  
Oleg Pustovyy ◽  
Ludmila Globa ◽  
Randy J Kulesza Jr ◽  
Iryna Sorokulova
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Novel Structure ◽  
Hematopoietic Stem Cell Niches ◽  
Cell Niche ◽  
Stem Cell Niches ◽  
Rat Bone

Stem cells are nurtured and regulated by a specialized microenvironment known as stem cell niche. While the functions of the niches are well defined, their structure and location remain unclear. We have identified in rat bone marrow, the seat of hematopoietic stem cells, extensively vascularized node-like compartments that fit the requirements for stem cell niche and which we called hemmules. Hemmules are round or oval structures of about one millimeter in diameter that are surrounded by a fine capsule, have afferent and efferent vessels, are filled with the extracellular matrix and mesenchymal, hematopoietic, endothelial stem cells, and contain cells of the megakaryocyte family, which are known for homeostatic quiescence and contribution to the bone marrow environment. We propose that hemmules are the long sought hematopoietic stem cell niches and that they are prototypical of stem cell niches in other organs.

scholarly journals The Crosstalk between Ovarian Cancer Stem Cell Niche and the Tumor Microenvironment

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Manuel Varas-Godoy ◽  
Gregory Rice ◽  
Sebastián E. Illanes
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Immune Cells ◽  
Stem Cell Niche ◽  
Small Population ◽  
The World ◽  
Cell Niche

Ovarian cancer is one of the most important causes of cancer-related death among women in the world. Despite advances in ovarian cancer treatment, 70–80% of women who initially respond to therapy eventually relapse and die. There is evidence that a small population of cells within the tumors called cancer stem cells (CSCs) could be responsible for treatment failure due to their enhanced chemoresistance and tumorigenicity. These cells reside in a niche that maintains the principal properties of CSCs. These properties are associated with the capacity of CSCs to interact with different cells of the tumor microenvironment including mesenchymal stem cells, endothelial cells, immune cells, and fibroblasts, promoting cancer progression. This interaction can be mediated by cytokines, growth factors, lipids, and/or extracellular vesicles released in the CSC niche. In this review, we will discuss how the interaction between ovarian CSCs and the tumor microenvironment can contribute to the maintenance of the CSC niche and consequently to tumor progression in ovarian cancer.

The Hematopoietic Stem Cell Niche.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-49-SCI-49
Author(s):  
Paul S. Frenette ◽  
Simón Méndez-Ferrer ◽  
Daniel Lucas-Alcaraz ◽  
Michela Batista ◽  
Sergio Lira ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Nerve Fibers ◽  
Cold Spring Harbor ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Cold Spring ◽  
Cell Niche

Abstract Abstract SCI-49 The concept of stem cell niche, proposed by Schofield 30 years ago, refers to the ability of the microenvironment to regulate stem cell fate. The niche provides critical signals allowing hematopoietic stem cells (HSC) to survive, and if so, whether to remain in or to leave the niche (mobilization), or whether to remain quiescent or divide. Some of these signals originate locally from the niche cell(s) but others are coming from afar. For example, we have found that signals from the sympathetic nervous system (SNS) promote the release of HSCs from the bone marrow (BM) niche. Under steady-state conditions, HSC egress in blood is orchestrated in a circadian manner where the fluctuations of circulating HSCs/progenitors are matched with antiphase oscillations in the expression of Cxcl12 mRNA in the BM microenvironment. These oscillations are entrained in the brain by the molecular clock through the local delivery of norepinephrine by SNS nerve terminals in the BM, and transmitted specifically by the β3 adrenergic receptor (Adrβ3) expressed on CXCL12-producing stromal cells, thereby leading to the cyclical degradation of the Sp1 transcription factor. In humans, the circadian release of HSC is inverted compared to rodents and may influence the stem cell yield even when mobilization is enforced by granulocyte colony-stimulating factor (G-CSF), suggesting the potential benefit to harvest HSCs in the clinic at the optimal circadian time. Given the coupling of nervous signals with the stem cell niche, we would expect that the stromal cell forming the niche would be intimately associated with nerve fibers. We have recently found using transgenic mice expressing the green fluorescent protein (GFP) under the Nestin promoter elements (Nes-Gfp), that GFP+ cells (referred to as Nestin+) form a HSC niche in the marrow. Nestin+ cells comprise a relatively small subset (0.08 ± 0.01%) of total BM nucleated cells that is anatomically and functionally associated with the vast majority of CD150+ CD48- Lin- HSCs near blood vessels and SNS fibers of the BM. Nestin+ niche cells express high levels of core genes regulating HSC retention (Cxcl12, Kit ligand, Vcam-1, Angiopoietin-1), and these genes are downregulated by mobilization induced by G-CSF or administration of Adrβ3 agonists. We have identified putative Nestin+ niche cells as bona fide mesenchymal stem cells (MSCs) since they can be propagated as single clonal spheres capable of self-renewal, dramatic in vivo expansion, and multipotency to form osteoblasts, adipocytes, and chondocytes. These data argue for a unique bone marrow niche formed by the pairing of the two rare stem cells, mesenchymal and hematopoietic, that exist in the marrow. Co-authors: Simón Méndez-Ferrer, Ph.D., Daniel Lucas, Ph.D., Michela Batista, Ph.D., Sergio A. Lira, M.D., Mount Sinai School of Medicine, New York, NY; Tatyana V. Michurina, Ph.D., Grigori N. Enikolopov Ph.D., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY Disclosures Frenette: Glycomimetic: Research Funding.

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