scholarly journals Role of Stem Cell Niche in the Maintenance of Hematopoietic Stem Cells

2007 ◽  
Vol 27 (2) ◽  
pp. 117-123 ◽  
Author(s):  
Fumio Arai ◽  
Toshio Suda
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Cell Niche

Identification of a Stroma-Mediated Wnt Signal Promoting Self-Renewal of Hematopoietic Stem Cells in the Stem Cell Niche.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2208-2208
Author(s):  
Young-Ju Kang ◽  
Eek-hoon Jho ◽  
Hanjun Kim ◽  
Gyeongsin Park ◽  
Jae-Seung Shim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Stem Cell Niche ◽  
Stable Form ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Stromal Component ◽  
Cell Niche

Abstract With contrasting results recently reported on the effects of b-catenin on hematopoietic stem cells (HSCs), the precise role of Wnt on HSC regulation remains in question. Here, we show that Wnt-b-catenin signaling triggers distinct biological effects on HSCs depending on the target of activation within the hematopoietic microenvironment. Retroviral transduction of a stable form of b-catenin into HSCs caused a loss of competitive repopulating units (CRUs) in a limiting-dilution assay, whereas stabilized b-catenin in stromal cells CRU frequencies of co-cultured HSCs with higher preservation of undifferentiated state and caused enhanced levels of reconstitution in a manner dependent on direct contact between HSC and stroma. The enhancing effect of b-catenin stabilized stroma on HSC was also observed for human HSCs exhibiting higher frequencies of lympho-myeloid repopulating cells after transplantation into NOD/SCID mice. Interestingly, gene expression patterns of Wnt signaling molecules revealed compartmentalization in a manner that canonical Wnt ligands were preferentially expressed in the hematopoietic cells while molecules for reception of the signal such as Frizzled receptors or their co-receptors are preferentially expressed in stromal component, suggesting the role of stromal component as a target of Wnt signals in the niche. Furthermore, b-catenin accumulated selectively in the endosteal stroma of the trabecule region in “stressed” marrows, but not in “steady-state” marrows. Taken together, these results suggest stroma-mediated Wnt signals may function as microenvironmental cues for HSC self-renewal in the stem cell niche.

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.

Thrombopoietin-Mpl Signal Induces Hematopoietic Stem Cells into Quiescent State in the Bone Marrow Niche.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 858-858
Author(s):  
Hiroki Yoshihara ◽  
Fumio Arai ◽  
Kentaro Hosokawa ◽  
Takao Takahashi ◽  
Hiroshi Miyazaki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Osteoblastic Cells ◽  
Bone Surface ◽  
Hematopoietic Stem ◽  
Cycle Arrest ◽  
Cell Niche

Abstract Hematopoietic stem cells (HSCs) have the ability to self-renew and to differentiate to produce multi-lineage blood cells throughout the lifetime of individuals. Maintenance of these stem cell activities depends on the balance of intrinsic and extrinsic factors. The factors which regulate HSCs are provided by a microenvironment called stem cell niche, and interactions between HSCs and stem cell niche is critical for the maintenance of stem cell activities. Recently, it has been reported that HSCs exist frequently aside of the trabecular bone surface in bone marrow (BM). We have previously reported that side-population (SP) in HSC fraction is in the G0 phase and anti-apoptotic stem cells, and contacts osteoblasts. (Arai et al., Cell 2004). To further investigate the regulation of quiescence, cell adhesion, and survival of HSCs, we tried to clone the quiescent HSCs specific molecules by microarray analysis of c-Kit+Sca-1+Lin− (KSL)-SP vs. non-SP cells. We identified that Mpl, thrombopoietin (Tpo) receptor, was highly expressed in SP cells compared to non-SP cells. Tpo/Mpl signal is known as a physiological regulator of megakaryopoiesis, but the role of Tpo/Mpl signal in the maintenance of HSCs remains elusive. In this study, we investigated the role of Tpo/Mpl signal on the regulation of HSCs in the niche. The frequency of Mpl+ cells in KSL, KSL-SP, and KSL-non SP cells were 50.4 %, 88.9 %, and 44.7 %, respectively. In addition, Tpo was expressed in osteoblastic cells in BM. Immunohistochemical staining of BM showed that Mpl+ HSCs adhered to the bone surface and bone-lining osteoblastic cells produced Tpo. These data suggest that Tpo/Mpl signal contributes to the HSCs-niche interaction. BM transplantation (BMT) assay demonstrated that Mpl+KSL cells showed high long-term reconstitution (LTR)-activity, whereas Mpl−KSL cells did not, suggesting that LTR-HSCs were enriched in Mpl+ fraction. To investigate the function of Tpo/Mpl signal in HSCs, we performed CAFC assay and LTC-IC assay in the presence of anti-Mpl neutralizing antibody (AMM2). Inhibition of Tpo/Mpl signal reduced cobblestone formation and reduced LTC-IC formation. These data suggest that Tpo/Mpl signal maintained immature phenotypes of HSCs in vitro. It was reported that Mpl deficient mice showed the defect of stem cell function. For rapid and transient inhibition of Mpl signaling in vivo, we administrated AMM2 into the adult mice. AMM2 did not affect the frequency of non-SP fraction, but transiently decreased frequency of SP in KSL after 6 days of injection. Moreover, the combination of AMM2 and 5-FU capacitated BMT without irradiation. In contrast, injection of Tpo increased KSL-SP cells. To understand the mechanism of Tpo/Mpl signal, we cultured Mpl+KSL cells in the presence of SCF and/or Tpo, and analyzed the gene expression. We found that Tpo treatment up-regulate β1-integrin and p57, but not p21, p27 or p18. As the up-regulation of p57 is essential for TGF-β induced cell cycle arrest in hematopoiesis, Tpo/Mpl signal may also be related to cell cycle arrest. Altogether, these data suggest that Tpo/Mpl signal regulates HSCs-niche interaction and enhanced the quiescence of HSCs.

Aging of hematopoietic stem cells is regulated by the stem cell niche

2008 ◽  
Vol 43 (11) ◽  
pp. 974-980 ◽  
Author(s):  
Wolfgang Wagner ◽  
Patrick Horn ◽  
Simone Bork ◽  
Anthony D. Ho
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Cell Niche

scholarly journals Long-Term Human Hematopoietic Stem Cell Culture in Microdroplets

Micromachines ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 90
Author(s):  
Pilar Carreras ◽  
Itziar González ◽  
Miguel Gallardo ◽  
Alejandra Ortiz-Ruiz ◽  
Maria Luz Morales ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Culture ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Stem Cell Culture ◽  
Cell Niche

We previously reported a new approach for micromanipulation and encapsulation of human stem cells using a droplet-based microfluidic device. This approach demonstrated the possibility of encapsulating and culturing difficult-to-preserve primary human hematopoietic stem cells using an engineered double-layered bead composed by an inner layer of alginate and an outer layer of Puramatrix. We also demonstrated the maintenance and expansion of Multiple Myeloma cells in this construction. Here, the presented microfluidic technique is applied to construct a 3D biomimetic model to recapitulate the human hematopoietic stem cell niche using double-layered hydrogel beads cultured in 10% FBS culture medium. In this model, the long-term maintenance of the number of cells and expansion of hHSCS encapsulated in the proposed structures was observed. Additionally, a phenotypic characterization of the human hematopoietic stem cells generated in the presented biomimetic model was performed in order to assess their long-term stemness maintenance. Results indicate that the ex vivo cultured human CD34+ cells from bone marrow were viable, maintained, and expanded over a time span of eight weeks. This novel long-term stem cell culture methodology could represent a novel breakthrough to improve Hematopoietic Progenitor cell Transplant (HPT) as well as a novel tool for further study of the biochemical and biophysical factors influencing stem cell behavior. This technology opens a myriad of new applications as a universal stem cell niche model potentially able to expand other types of cells.

G-CSF Induced Expansion and Mobilization of Hematopoietic Stem Cells Is Altered by the Matrix Protein Osteopontin.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1400-1400
Author(s):  
Randolf Forkert ◽  
Yon Ko ◽  
Thomas Neuhaus ◽  
Elisabeth Gruenewald ◽  
Silke Schoeneborn ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Stem Cell Niche ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Cell Mobilization ◽  
Cell Niche

Abstract Stem cells reside in a physical microenvironment or niche where a balance of signals controls their proliferation, differentiation and death. Components of the specialized microenvironment have generally been defined in terms of cells and signaling pathways affecting stem cell maintenance or expansion. We have defined a role for a matrix glycoprotein that provides a constraining function on hematopoietic stem cells within the bone marrow microenvironment. Osteopontin (OPN) is an abundant glycoprotein in bone that modifies primitive hematopoietic cell number and function in a stem cell non-autonomous manner. Here we analyzed the role of OPN for regulating stem cell mobilization and pool size in times of G-CSF induced marrow stress, a context close to the clinical setting of stem cell mobilization not well understood so far. Bone marrow stromal cells show an enhanced expression of OPN under stimulation with G-CSF, which prompted us to analyze the role of OPN in G-CSF mediated activation of the stem cell niche. First we treated OPN deficient mice and their wild-type littermates with G-CSF for 5 days. We could observe a significant increased stem cell fraction in the peripheral blood and in the bone marrow in the absence of OPN in comparison to the wild-type controls. To evaluate, if this effect is stroma dependent, we first transplanted wild-type bone marrow into wild-type or OPN-deficient recipients. 6 weeks after transplantation we treated these mice with G-CSF for 5 days and analyzed the peripheral blood and the bone marrow for the contents of primitive hematopoietic cells. Here we could detect a significantly increased stem cell fraction in peripheral blood and bone marrow of the OPN−/− recipients in comparison to wild type controls detected by FACS and functional in vitro stem cell assays. We then transplanted the stressed bone marrow in a competitive repopulation assay into wild-type recipients and observed a significant increase of CD45.2 cells from OPN−/− recipient mice up to 12 weeks after transplantation in comparison to wild-type controls, demonstrating an enhanced G-CSF induced expansion of hematopioetic stem cells in the OPN-deficient stem cell niche. Furthermore, we could observe an enhanced expression of Angiopoietin and N-Cadherin in OPN-deficient bone marrow stromal cells after stimulation with G-CSF in comparison to wild-type controls, supporting the stroma dependent expansion of stem cells in the absence of OPN in the G-CSF stimulated stem cell niche. Therefore, OPN is a restricting element of the stem cell niche limiting the size of the stem cell pool and may provide a dynamic mechanism by which excess stem cell expansion is prevented during times of niche stimulation. These findings may provide new insight into expansion and mobilization of hematopoietic stem cells by G-CSF mediated by components of the stem cell niche.

scholarly journals Biomimetic reconstruction of the hematopoietic stem cell niche for in vitro amplification of human hematopoietic stem cells

PLoS ONE ◽  
2020 ◽  
Vol 15 (6) ◽  
pp. e0234638 ◽  
Author(s):  
L. Marx-Blümel ◽  
C. Marx ◽  
F. Weise ◽  
J. Frey ◽  
B. Perner ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche
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