scholarly journals Myelodysplastic Cells in Patients Reprogram Mesenchymal Stromal Cells to Establish a Transplantable Stem Cell Niche Disease Unit

2014 ◽  
Vol 14 (6) ◽  
pp. 824-837 ◽  
Author(s):  
Hind Medyouf ◽  
Maximilian Mossner ◽  
Johann-Christoph Jann ◽  
Florian Nolte ◽  
Simon Raffel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Cell Niche ◽  
Disease Unit

scholarly journals Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells

2019 ◽  
Vol 21 (5) ◽  
pp. 560-567 ◽  
Author(s):  
Fumio Nakahara ◽  
Daniel K. Borger ◽  
Qiaozhi Wei ◽  
Sandra Pinho ◽  
Maria Maryanovich ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Haematopoietic Stem Cell ◽  
Cell Niche

scholarly journals Human aplastic anaemia-derived mesenchymal stromal cells form functional haematopoietic stem cell niche in vivo

2016 ◽  
Vol 179 (4) ◽  
pp. 669-673 ◽  
Author(s):  
Ilaria M. Michelozzi ◽  
Alice Pievani ◽  
Fabio Pagni ◽  
Laura Antolini ◽  
Marta Verna ◽  
...  
Keyword(s):  
Stem Cell ◽  
Aplastic Anaemia ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Haematopoietic Stem Cell ◽  
Cell Niche

Disruption of Bis Leads to Deterioration of Mesenchymal Stromal Cells Predominantly Affecting Vascular Compartment of Hematopoietic Stem Cell Niche.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3627-3627
Author(s):  
Il-Hoan Oh ◽  
Kyong-Rim Kwon ◽  
Ji-Yeon Ahn ◽  
Myungshin Kim ◽  
Jeong-Hwa Lee
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Cellular Stress ◽  
Hematopoietic Stem ◽  
Stromal Component ◽  
Cell Niche ◽  
Vascular Compartment

Abstract Abstract 3627 Poster Board III-563 The stem cell niche plays an important role in the microenvironmental regulation of hematopoietic stem cells (HSCs), but the integration of niche activity remains poorly understood. In this study explored the hematopoietic defect of mice disrupted with Bis/BAG-3/CAIR-1, a protein related to apoptosis and response to cellular stress and show that functional loss of bis leads to series of hematopoietic derangements due to perturbation of vascular stem cell niche. First, mice with targeted disruption of bis (bis−/−) exhibited severe hypocellularity in the bone marrows and spleen starting from 16 days after birth. Affected mice exhibited loss of primitive neonatal HSCs (CD34+Lin-Sca-1+c-kit+) and defect in early stage B-lymphopoiesis including common lymphoid progenitors (IL-17R+LSK), pre-B and pro-B cell populations, but not for mature recycling B-lymphocytes (IgD+B220+). However, this hematological defect of bis−/− mice was not reproduced when bis−/− bone marrow cells were transplanted into wild-type (WT) recipients, pointing to the microenvironmental origin of the phenotypes. Subsequent analysis of bis−/− mice bone marrow revealed a characteristic defect in the mesenchymal stromal component that included a quantitative loss of stromal cells (CD45-CD31-TER119-CD105+) in the bone marrows and rapid sensescence of stromal cells comprising colony forming unit-fibroblast (CFU-F) when re-plated in the ex-vivo culture. Moreover, mesenchymal stromal cells expressing CXCL-12 or IL-7 was lost in the affected bone marrows with lowered density of vascular development, together indicating a perturbation of peri-vascular stem cell niche in the bone marrow. In contrast, no abnormalities were observed in the growth and hematopoietic supporting activities of osteoblasts obtained from bis−/− mice. Collectively, these results indicate that Bis functions to mediate cellular regulation of the stem cell niche activities selectively on the vascular compartment without affecting osteoblastic niche, and suggest that Bis may serve as a molecule that can bridge the microenvironment niche and cellular stress/apoptotic signals during the in-vivo orchestration of hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

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 A Substrate-Mimicking Basement Membrane Drives the Organization of Human Mesenchymal Stromal Cells and Endothelial Cells Into Perivascular Niche-Like Structures

2021 ◽  
Vol 9 ◽  
Author(s):  
Valeria Perugini ◽  
Matteo Santin
Keyword(s):  
Bone Marrow ◽  
Tissue Culture ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Tissue Culture Plastic ◽  
Histological Features ◽  
Cell Niche ◽  
3D Spheroids

Extracellular matrix-derived products (e.g. Matrigel) are widely used for in vitro cell cultures both as two-dimensional (2D) substrates and as three-dimensional (3D) encapsulation gels because of their ability to control cell phenotypes through biospecific cues. However, batch-to-batch variations, poor stability, cumbersome handling, and the relatively high costs strictly limit their use. Recently, a new substrate known as PhenoDrive-Y has been used as 2D coating of tissue culture plastic showing to direct the bone marrow mesenchymal stromal cells (MSCs) toward the formation of 3D spheroids. When organized into 3D spheroids, the MSCs expressed levels of pluripotency markers and of paracrine angiogenic activity higher than those of the MSCs adhering as fibroblast-like colonies on tissue culture plastic. The formation of the spheroids was attributed to the properties of this biomaterial that resemble the main features of the basement membrane by mimicking the mesh structure of collagen IV and by presenting the cells with orderly spaced laminin bioligands. In this study, PhenoDrive-Y was compared to Matrigel for its ability to drive the formation of perivascular stem cell niche-like structures in 2D co-culture conditions of human endothelial cells and adult bone marrow MSCs. Morphological analyses demonstrated that, when compared to Matrigel, PhenoDrive-Y led endothelial cells to sprout into a more consolidated tubular network and that the MSCs nestled as compact spheroids above the anastomotic areas of this network resemble more closely the histological features of the perivascular stem cell niche. A study of the expressions of relevant markers led to the identification of the pathways linking the PhenoDrive-Y biomimicking properties to the acquired histological features, demonstrating the enhanced levels of stemness, renewal potential, predisposition to migration, and paracrine activities of the MSCs.

Mir-886-3p Contributes to the Regulation of the hematopoietic microenvironment by down-Regulating SDF-1α (CXCL12).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 561-561
Author(s):  
Manoj M Pillai ◽  
Xiaodong Yang ◽  
Mineo Iwata ◽  
Lynne Bemis ◽  
Beverly Torok-Storb
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Expression Profiles ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Proliferation And Differentiation ◽  
Cell Niche ◽  
Angiopoietin 1

Abstract Abstract 561 Two functionally distinct stromal cell lines were isolated from a primary long term culture (LTC) established from aspirated human marrow. Designated HS5 and HS27a, the lines were immortalized and extensively characterized including expression profiles for both messenger (mRNA) and micro-RNA (miRNA, a recently described class of small non-coding RNAs that regulate gene expression by binding to target mRNAs to prevent their translation). HS5 was found to secrete growth factors that stimulate proliferation and differentiation of hematopoietic progenitors (G-CSF, IL-6, IL-1α and IL1β), whereas HS27a expresses activities associated with the stem cell niche (SDF-1αa, angiopoietin-1 etc). In keeping with this HS5 conditioned media stimulated proliferation and differentiation of isolated CD34+ cells whereas HS27a supported CD34+ cells in an undifferentiated state. When cultured together to better mimic in vivo cell-cell interactions, the gene expression of HS27a and HS5 combined differed from the expected sum of the two parts, exemplified by the 5-fold down regulation of SDF-1α. Comparisons of miRNA expression profiles of HS5 and HS27a determined that mir-886-3p, (previously described by deep sequencing of small RNA libraries) was expressed > 40 fold in HS5 compared to HS27a, this was then confirmed by quantitative RT-PCR. Given the abundance of mir-886-3p and the possibility that it could be secreted by HS5 and taken up by cells in contact with HS5, we tested its effect on gene expression in HS27a. Transcript levels of genes associated with the stem cell niche (Jagged1, BMP4, Angiopoietin-1, SDF-1α, VCAM-1 and N-Cadherin) were determined by quantitative RT-PCR after direct transfection of mir-886-3p precursors into HS27a cells and compared to appropriate controls. Results show SDF-1α mRNA expression was down-regulated by as much as 8 fold 3 days after transfection. Levels of secreted SDF-1α in culture media, as determined by ELISA, were also decreased. Since SDF-1α is a chemokine known to be critical for the homing of hematopoietic stem and progenitor cells to their niche, the functional significance of the SDF-1α down-regulation by mir-886-3p was confirmed by decreased chemotaxis of T-lymphocytic cells (Jurkat) following miRNA transfection of stromal cells. To determine if mir-886-3p directly effects the SDF-1α transcript, the 1.5 kbp 3'untranslated region (UTR) of SDF-1α gene was cloned downstream of the luciferase gene, and co-transfected with mir-886-3p into HS27a cells. Results showed the luciferase activity was down-regulated greater than 50% in the presence of mir-886-3p, suggesting a direct effect on the SDF-1 α transcript. Given the concern over the relevance of immortalized cell lines we investigated Mir-886-3p expression in primary marrow stromal cells at early passage sorted on the basis of +/- expression of CD146. (CD146 or MCAM has been reported to define a population that supports the hematopoietic stem/ precursor cell niche and is expressed by HS27a and not HS5 cells). Results indicated that the CD146+ stromal cells had significantly lower expression of mir-886-3p when compared to CD146- cells. In summary, these data suggest a role for miRNA in modulating the expression of gene products that are associated with the hematopoietic stem cell niche. Disclosures: No relevant conflicts of interest to declare.

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