scholarly journals Mimicking the functional hematopoietic stem cell niche in vitro: recapitulation of marrow physiology by hydrogel-based three-dimensional cultures of mesenchymal stromal cells

Haematologica ◽  
2011 ◽  
Vol 97 (5) ◽  
pp. 651-660 ◽  
Author(s):  
M. B. Sharma ◽  
L. S. Limaye ◽  
V. P. Kale
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Three Dimensional ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche

scholarly journals Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Boyan Wang ◽  
Yi Wang ◽  
Hainan Chen ◽  
Senyu Yao ◽  
Xiaofan Lai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Cancer Cachexia ◽  
Tgfβ Signaling ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Cancer Related Anemia

Abstract Background Cancer cachexia is a wasting syndrome that is quite common in terminal-stage cancer patients. Cancer-related anemia is one of the main features of cancer cachexia and mostly results in a poor prognosis. The disadvantages of the current therapies are obvious, but few new treatments have been developed because the pathological mechanism remains unclear. Methods C57BL/6 mice were subcutaneously injected with Lewis lung carcinoma cells to generate a cancer-related anemia model. The treated group received daily intraperitoneal injections of SB505124. Blood parameters were determined with a routine blood counting analyzer. Erythroid cells and hematopoietic stem/progenitor cells were analyzed by flow cytometry. The microarchitecture changes of the femurs were determined by micro-computed tomography scans. Smad2/3 phosphorylation was analyzed by immunofluorescence and Western blotting. The changes in the hematopoietic stem cell niche were revealed by qPCR analysis of both fibrosis-related genes and hematopoietic genes, fibroblastic colony-forming unit assays, and lineage differentiation of mesenchymal stromal cells. Results The mouse model exhibited hematopoietic suppression, marked by a decrease of erythrocytes in the peripheral blood, as well as an increase of immature erythroblasts and reduced differentiation of multipotent progenitors in the bone marrow. The ratio of bone volume/total volume, trabecular number, and cortical wall thickness all appeared to decrease, and the increased osteoclast number has led to the release of latent TGFβ and TGFβ signaling over-activation. Excessive TGFβ deteriorated the hematopoietic stem cell niche, inducing fibrosis of the bone marrow as well as the transition of mesenchymal stromal cells. Treatment with SB505124, a small-molecule inhibitor of TGFβ signaling, significantly attenuated the symptoms of cancer-related anemia in this model, as evidenced by the increase of erythrocytes in the peripheral blood and the normalized proportion of erythroblast cell clusters. Meanwhile, hindered hematopoiesis and deteriorated hematopoietic stem cell niche were also shown to be restored with SB505124 treatment. Conclusion This study investigated the role of TGFβ released by bone remodeling in the progression of cancer-related anemia and revealed a potential therapeutic approach for relieving defects in hematopoiesis.

Matrix Glycoprotein Osteopontin Is a Stem Cell Niche Constituent That Constrains the Hematopoietic Stem Cell Pool Size.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 664-664 ◽  
Author(s):  
Sebastian Stier ◽  
Yon Ko ◽  
Randolf Forkert ◽  
Christoph Lutz ◽  
Thomas Neuhaus ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Stem Cell Pool

Abstract Stem cells reside in a physical niche where a balance of signals controls their growth, differentiation and death. Niche components have generally been defined in terms of cells and positive effects on stem cell maintenance or expansion. Here we define a role for a matrix glycoprotein that provides a constraining function in the hematopoietic stem cell niche. Osteopontin (OPN) is an abundant glycoprotein in bone that can function as either cytokine or cell adhesion mediator. It is known to be produced by multiple cells types including osteoblasts, cells recently defined to be a regulatory component of the hematopoietic stem cell niche. Using studies combining OPN deficient mice and exogenous OPN, we demonstrate that OPN modifies primitive hematopoietic cell numbers and function. In OPN deficient mice, increased primitive cell numbers were observed in vivo associated with reduced progenitors and reduced primitive cell apoptotic fraction. To determine whether the effect of OPN deficiency was stroma dependent, we performed in vitro stem cell assays on OPN−/− stroma and observed greater LTC-IC supportive capacity compared with wild type stroma. Furthermore, OPN−/− recipients showed a significantly higher proportion of hematopoietic stem cells after transplantation of OPN+/+ bone marrow in comparison to wild-type recipients, indicating that the OPN null microenvironment was sufficient to increase stem cell number. A reduction in apoptotic fraction was seen in primitive cells in the OPN−/− recipient marrows. A role for OPN in apoptosis was confirmed by exogenous OPN in in-vitro studies. Hypothesizing that OPN may serve as a physiologic constraint on stem cell pool size, we compared OPN−/− with wild type animals following parathyroid hormone activation of the stem cell niche. The expansion of stem cells by PTH was superphysiologic in the absence of OPN. Therefore, OPN is a restricting element of the stem cell niche, limiting the number of stem cells produced by niche activation. Extracellular matrix components such as OPN may serve as modulable, regulatory participants in the stem cell niche.

scholarly journals Modeling Osteoclast Defect and Altered Hematopoietic Stem Cell Niche in Osteopetrosis with Patient-Derived iPSCs

2021 ◽  
Author(s):  
Inci Cevher Zeytin ◽  
Berna Alkan ◽  
Cansu Ozdemir ◽  
Duygu Cetinkaya ◽  
FATMA VISAL OKUR
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Hematopoietic Niche

Abstract Background Patients with osteopetrosis present with defective bone resorption caused by the lack of osteoclast activity and hematopoietic alterations, but their bone marrow hematopoietic stem/progenitor cell and osteoclast contents might be different. Osteoclasts recently have been described as the main regulators of HSCs niche, however, their exact role remains controversial due to the use of different models and conditions. Investigation of their role in hematopoietic stem cell niche formation and maintenance in osteopetrosis patients would provide critical information about the mechanisms of altered hematopoiesis. We used patient-derived induced pluripotent stem cells (iPSCs) to model osteoclast defect and hematopoietic niche compartments in vitro. Methods iPSCs were generated from peripheral blood mononuclear cells of patients carrying TCIRG1 mutation. iPSC lines were differentiated first into hematopoietic stem cells-(HSCs), and then into myeloid progenitors and osteoclasts using a step-wise protocol. Then, we established different co-culture conditions with bone marrow-derived hMSCs and iHSCs of osteopetrosis patients as an in vitro hematopoietic niche model to evaluate the interactions between osteopetrotic-HSCs and bone marrow-derived MSCs as osteogenic progenitor cells. Results We first demonstrated myeloid-skewed hematopoietic differentiation potential of osteopetrotic iPSC-derived hematopoietic progenitors and phenotypically normal and functionally defective osteoclast formation. Upon co-culture with healthy iHSCs, the expression of the genes involved in HSC homing and maintenance (Ang-1, Sdf-1, Jagged-1, N-Cadherine, Kit-L, Opn) in osteopetrotic MSCs which revealed impaired osteogeneic differentiation, as well as their attraction ability over HSCs recovered significantly. Similar change in the phenotype of osteopetrotic iHSCs occured when they interacted with healthy MSCs. Conclusion Our results establish significant alterations in both MSC and HSC compartments of the hematopoietic niche in osteopetrosis patients, which are restored with normal MSC activity supporting the role of defective osteoclasts in all these processes.

scholarly journals Rebuilding the hematopoietic stem cell niche: recent developments and future prospects

2021 ◽  
Author(s):  
Chandralekha Chatterjee ◽  
Peter Schertl ◽  
Miriam Frommer ◽  
Anita Ludwig-Husemann ◽  
Anna Mohra ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Future Prospects ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Recent Developments ◽  
Cell Niche

scholarly journals In memory of Paul Sylvain Frenette, a pioneering explorer of the hematopoietic stem cell niche who left far too early

2021 ◽  
Author(s):  
Jean-Pierre Lévesque ◽  
Louise E Purton ◽  
Andrés Hidalgo ◽  
Leonard Zon ◽  
Yoshio Katayama ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell 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.

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