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 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 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.

scholarly journals P04.45 Periarteriolar glioblastoma stem cell niches express bone marrow hematopoietic stem cell niche proteins

2018 ◽  
Vol 20 (suppl_3) ◽  
pp. iii289-iii289
Author(s):  
V V V Hira ◽  
J R Wormer ◽  
H Kakar ◽  
B Breznik ◽  
B van der Swaan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Glioblastoma Stem Cell ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Stem Cell Niches

scholarly journals Author Correction: Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche

2019 ◽  
Vol 25 (4) ◽  
pp. 701-701 ◽  
Author(s):  
Maria Maryanovich ◽  
Ali H. Zahalka ◽  
Halley Pierce ◽  
Sandra Pinho ◽  
Fumio Nakahara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Nerve Degeneration ◽  
Adrenergic Nerve ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche

Role of Integrins in Adhesion of Hematopoietic Progenitor Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4263-4263
Author(s):  
Shawdee Eshghi ◽  
Jing Zhang ◽  
Linda G. Griffith ◽  
Harvey F. Lodish
Keyword(s):  
Stem Cell ◽  
Stem Cell Niche ◽  
Fetal Liver ◽  
Hematopoietic Stem ◽  
Cell Matrix ◽  
Hematopoietic Stem Cell Niche ◽  
Matrix Interactions ◽  
Cell Niche ◽  
Cell Matrix Interactions

Abstract The hematopoietic stem cell niche is the set of soluble growth factors, cell-cell and cell-matrix interactions that contribute to stem cell self renewal in the bone marrow. While cytokines and cell-cell interactions have been well documented, cell-matrix interactions in the niche are less understood. Integrins are a class of highly conserved cell adhesion molecules that are important in hematopoietic development and homing. However the specific role of integrins in mediating adhesion to extracellular matrix in the hematopoietic stem cell niche is unknown. The terminal stages of erythropoiesis in the fetal liver provide a good model system with which to develop several of the assays to be used with HSCs. Using flow cytometry, murine fetal liver erythroid progenitors can be separated at four distinct stages of development based on expression of CD71 and Ter119. Further FACS and quantitative PCR analysis revealed that α4β1 integrin is significantly downregulated over the course of erythroid differentiation. Using a centrifugation assay, we determined that this change is accompanied by a loss of adhesion to fibronectin, and that adhesion to fibronectin is blocked by addition of anti-integrin antibodies. Finally, fetal liver progenitor cells adhered to comb co-polymer surfaces engineered to present peptides specifically recognized by α4β1 integrins. By determining the integrin profile expressed by hematopoietic stem cells and measuring stem cell adhesion to ECM in a similar manner, we can begin to understand how these specific interactions present developmental cues important to maintaining the stem cell phenotype in vivo, in addition to leading to design parameters for ex vivo culture systems.

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