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Hematopoietic niche

Jennifer L Gori, Jason M Butler, Balvir Kunar, Michael G Poulos, Michael Ginsberg, Daniel J Nolan, Zachary K Norgaard, Jennifer E Adair, Shahin Rafii, Hans-Peter Kiem
: : Successful expansion of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) would benefit many HSPC transplantation and gene therapy/editing applications. However, current expansion technologies have been limited by a loss of multipotency and self-renewal properties ex vivo. We hypothesized that an ex vivo vascular niche would provide prohematopoietic signals to expand HSPCs while maintaining multipotency and self-renewal. To test this hypothesis, BM autologous CD34(+) cells were expanded in endothelial cell (EC) coculture and transplanted in nonhuman primates...
October 14, 2016: Stem Cells Translational Medicine
Áine M Prendergast, Andrea Kuck, Mieke van Essen, Simon Haas, Sandra Blaszkiewicz, Marieke A G Essers
In the bone marrow, endothelial cells are a major component of the hematopoietic stem cell vascular niche and are a first line of defense against inflammatory stress and infection. The primary response of an organism to infection involves the synthesis of immune-modulatory cytokines, including interferon alpha. In the bone marrow, interferon alpha induces rapid cell cycle entry of hematopoietic stem cells in vivo However, the effect of interferon alpha on bone marrow endothelial cells has not been described...
October 14, 2016: Haematologica
Antonella Antonelli, Willy A Noort, Jenny Jaques, Bauke de Boer, Regina de Jong-Korlaar, Annet Z Brouwers-Vos, Linda Lubbers-Aalders, Jeroen F van Velzen, Andries C Bloem, Huipin Yuan, Joost D de Bruijn, Gert J Ossenkoppele, Anton C M Martens, Edo Vellenga, Richard W J Groen, Jan Jacob Schuringa
In order to begin to understand mechanisms that regulate self-renewal, differentiation and transformation of human hematopoietic stem cells, or to evaluate the efficacy of novel treatment modalities, stem cells need to be studied in their own species-specific microenvironment. By implanting ceramic scaffolds coated with human mesenchymal stromal cells (MSCs) into immune deficient mice we mimic the human bone marrow niche. Thus, we have established a human leukemia xenograft mouse model in which a large cohort of patient samples successfully engrafted covering all important genetic and risk subgroups...
October 12, 2016: Blood
Fumio Arai
Hematopoietic stem cells (HSCs) are characterized by their ability to self-renew and differentiate into all blood lineage cells. The fate decisions of HSCs (self-renewal versus differentiation) are made through the process of cell division and are often compared to "birth" and "death". Stem cells give rise to undifferentiated stem cells (birth) or differentiate into progenitor cells (death). This process is regulated by asymmetric/symmetric divisions of HSCs. It has been proposed that fate determination occurs as a stochastic process and that individual stem cell dynamics are randomly regulated...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Marco Saia, Alberto Termanini, Nicoletta Rizzi, Massimiliano Mazza, Elisa Barbieri, Debora Valli, Paolo Ciana, Alicja M Gruszka, Myriam Alcalay
The AML1/ETO fusion protein found in acute myeloid leukemias functions as a transcriptional regulator by recruiting co-repressor complexes to its DNA binding site. In order to extend the understanding of its role in preleukemia, we expressed AML1/ETO in a murine immortalized pluripotent hematopoietic stem/progenitor cell line, EML C1, and found that genes involved in functions such as cell-to-cell adhesion and cell motility were among the most significantly regulated as determined by RNA sequencing. In functional assays, AML1/ETO-expressing cells showed a decrease in adhesion to stromal cells, an increase of cell migration rate in vitro, and displayed an impairment in homing and engraftment in vivo upon transplantation into recipient mice...
October 7, 2016: Scientific Reports
Mateusz Adamiak, Malwina Suszynska, Ahmed Abdel-Latif, Ahmed Abdelbaset-Ismail, Janina Ratajczak, Mariusz Z Ratajczak
Migration and bone marrow (BM) homing of hematopoietic stem progenitor cells (HSPCs) is regulated by several signaling pathways, and here we provide evidence for the involvement in this process of hematopoietic-specific phospholipase C-β2 (PLC-β2). This enzyme is involved in release of intracellular calcium and activation of protein kinase C (PKC). Recently we reported that PLC-β2 promotes mobilization of HSPCs from BM into peripheral blood (PB), and this effect is mediated by the involvement of PLC-β2 in the release of proteolytic enzymes from granulocytes and its role in disintegration of membrane lipid rafts...
October 4, 2016: Stem Cell Reviews
Yulin Xu, Wei Shan, Xia Li, Binsheng Wang, Senquan Liu, Yebo Wang, Yan Long, Ruxiu Tie, Limengmeng Wang, Shuyang Cai, Hao Zhang, Yu Lin, Mingming Zhang, Weiyan Zheng, Yi Luo, Xiaohong Yu, Jiing-Kuan Yee, Junfeng Ji, He Huang
BACKGROUND: The efficient generation of hematopoietic stem cells (HSCs) from human-induced pluripotent stem cells (iPSCs) holds great promise in personalized transplantation therapies. However, the derivation of functional and transplantable HSCs from iPSCs has had very limited success thus far. METHODS: We developed a synthetic 3D hematopoietic niche system comprising nanofibers seeded with bone marrow (BM)-derived stromal cells and growth factors to induce functional hematopoietic cells from human iPSCs in vitro...
September 29, 2016: Journal of Hematology & Oncology
Suprita Ghode, Manmohan Bajaj, Rohan Kulkarni, Lalita S Limaye, Yogesh Shouche, Vaijayanti Prakash Kale
Marrow adipocytes pose a significant problem in post-transplant regeneration of hematopoiesis owing to their negative effects on regeneration of hematopoiesis. However, the precise mechanism operative in this negative regulation is not clear. Here we show that marrow adipocytes express Neuropilin1 (NRP1) as a function of differentiation, and inhibit regeneration of hematopoiesis by three principal mechanisms; one, by inducing apoptosis in hematopoietic stem/progenitor cells (HSPCs) via death receptor-mediated pathway, two, by down-regulating CXCR4 expression on the HSPCs via ligand-mediated internalization, and three, by secreting copious amounts of Transforming Growth Factor β1 (TGFβ1), a known inhibitor of hematopoiesis...
September 27, 2016: Stem Cells and Development
Neta Soffer-Tsur, Dan Peer, Tal Dvir
The success of hematopoietic stem cells (HSCs) transplantation is limited due to the low number of HSCs received from donors. In vivo, HSCs reside within a specialized niche inside the 3D porous spongy bone. The natural environment in the niche is composed of structural proteins, glycosaminoglycans (GAGs) and soluble factors that control cells fate. However, the designed scaffolds for in vitro culture do not fairly recapitulate this microenvironment and cannot efficiently control HSCs fate. Here we report on the development of new omental ECM-based 3D macroporous sponges for hematopoietic cell culture...
September 23, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Noemi A Zambetti, Zhen Ping, Si Chen, Keane J G Kenswil, Maria A Mylona, Mathijs A Sanders, Remco M Hoogenboezem, Eric M J Bindels, Maria N Adisty, Paulina M H Van Strien, Cindy S van der Leije, Theresia M Westers, Eline M P Cremers, Chiara Milanese, Pier G Mastroberardino, Johannes P T M van Leeuwen, Bram C J van der Eerden, Ivo P Touw, Taco W Kuijpers, Roland Kanaar, Arjan A van de Loosdrecht, Thomas Vogl, Marc H G P Raaijmakers
Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress...
September 10, 2016: Cell Stem Cell
Naoya Uchida, R Patrick Weitzel, Anna Shvygin, Luke P Skala, Lydia Raines, Aylin C Bonifacino, Allen E Krouse, Mark E Metzger, Robert E Donahue, John F Tisdale
Reduced intensity conditioning (RIC) is desirable for hematopoietic stem cell (HSC) gene therapy applications. However, low gene marking was previously observed in gene therapy trials, suggesting that RIC might be insufficient for (i) opening niches for efficient engraftment and/or (ii) inducing immunological tolerance for transgene-encoded proteins. Therefore, we evaluated both engraftment and tolerance for gene-modified cells using our rhesus HSC gene therapy model following RIC. We investigated a dose de-escalation of total body irradiation (TBI) from our standard dose of 10Gy (10, 8, 6, and 4Gy), in which rhesus CD34(+) cells were transduced with a VSVG-pseudotyped chimeric HIV-1 vector encoding enhanced green fluorescent protein (GFP) (or enhanced yellow fluorescent protein (YFP))...
2016: Molecular Therapy. Methods & Clinical Development
Lidan Zhao, Linfang Huang, Xuan Zhang
Rapid progress has been made in exploring the connections between the skeletal system and the immune system over the past decade. Bone tissue forms developmental niches for hematopoietic stem cells, and activated immune cells are involved in bone metabolism regulation and are potent mediators of osteoporosis and bone erosion under pathological conditions. The interdisciplinary field of osteoimmunology has emerged to pool the knowledge of the interdependence of these two systems, including the shared ligands and receptors, their crosstalk and interaction, and common intracellular signaling pathways with bidirectional influence...
September 20, 2016: Science China. Life Sciences
Aimee G Kim, Jesse D Vrecenak, Matthew M Boelig, Linda Eissenberg, Michael P Rettig, John S Riley, Matthew S Holt, Michael A Conner, Stavros P Loukogeorgakis, Haiying Li, John F DiPersio, Alan W Flake, William H Peranteau
In utero hematopoietic cell transplantation (IUHCT) is a novel nonmyeloablative approach that results in donor specific tolerance and mixed allogeneic chimerism. Clinical application is limited by low levels of donor cell engraftment. Competition from endogenous hematopoietic stem cells (HSCs) for limited "space" in fetal hematopoietic organs remains a significant barrier to successful IUHCT. AMD3100, a CXCR4 inhibitor, and firategrast, an α4β1 and α4β7 integrin inhibitor (α4β1/7) have been shown to disrupt HSC retention in the postnatal hematopoietic niche (HN)...
September 20, 2016: Blood
Juo-Chin Yao, Daniel C Link
Hematopoietic stem cell (HSC) proliferation, self-renewal, and trafficking are dependent, in part, upon signals generated by stromal cells in the bone marrow. Stromal cells are organized into niches that support specific subsets of hematopoietic progenitors. There is emerging evidence that malignant hematopoietic cells may generate signals that alter the number and/or function of specific stromal cell populations in the bone marrow. At least in some cases, the resulting alterations in the bone marrow microenvironment confer a competitive advantage to the malignant HSC and progenitor cells and/or render them less sensitive to chemotherapy...
September 19, 2016: Stem Cells
Joshua P Sasine, Kelly T Yeo, John P Chute
: : The functions of endothelial cells (ECs) in regulating oxygen delivery, nutrient exchange, coagulation, and transit of inflammatory cells throughout the body are well--established. ECs have also been shown to regulate the maintenance and regeneration of organ-specific stem cells in mammals. In the hematopoietic system, hematopoietic stem cells (HSCs) are dependent on signals from the bone marrow (BM) vascular niche for their maintenance and regeneration after myelosuppressive injury...
September 13, 2016: Stem Cells Translational Medicine
Julianne N P Smith, Vikramjit S Kanwar, Katherine C MacNamara
Aplastic anemia (AA) occurs when the bone marrow fails to support production of all three lineages of blood cells, which are necessary for tissue oxygenation, infection control, and hemostasis. The etiology of acquired AA is elusive in the vast majority of cases but involves exhaustion of hematopoietic stem cells (HSC), which are usually present in the bone marrow in a dormant state, and are responsible for lifelong production of all cells within the hematopoietic system. This destruction is immune mediated and the role of interferons remains incompletely characterized...
2016: Frontiers in Immunology
Thomas Höfer, Hans-Reimer Rodewald
The hematopoietic stem cell (HSC) compartment must be maintained life-long, while being replenishable only from within. HSC proliferation can compensate for cell loss by differentiation, by cell death, or by mobilization from the bone marrow niches, but the relative use of proliferation to compensate for these distinct depletion sources is unclear. Classifications of HSC states (e.g., as active, dormant, quiescent or parsimonious) have mostly been based on HSC proliferation rather than on actual differentiation arising from HSC...
September 10, 2016: Current Opinion in Cell Biology
Deepa Bhartiya, Ambreen Shaikh, Sandhya Anand, Hiren Patel, Sona Kapoor, Kalpana Sriraman, Seema Parte, Sreepoorna Unni
BACKGROUND: Both pluripotent very small embryonic-like stem cells (VSELs) and induced pluripotent stem (iPS) cells were reported in 2006. In 2012, a Nobel Prize was awarded for iPS technology whereas even today the very existence of VSELs is not well accepted. The underlying reason is that VSELs exist in low numbers, remain dormant under homeostatic conditions, are very small in size and do not pellet down at 250-280g. The VSELs maintain life-long tissue homeostasis, serve as a backup pool for adult stem cells and are mobilized under stress conditions...
September 10, 2016: Human Reproduction Update
Noah I Hornick, Ben Doron, Sherif Abdelhamed, Jianya Huan, Christina A Harrington, Rongkun Shen, Xiaolu A Cambronne, Santhosh Chakkaramakkil Verghese, Peter Kurre
Exosomes are paracrine regulators of the tumor microenvironment and contain complex cargo. We previously reported that exosomes released from acute myeloid leukemia (AML) cells can suppress residual hematopoietic stem and progenitor cell (HSPC) function indirectly through stromal reprogramming of niche retention factors. We found that the systemic loss of hematopoietic function is also in part a consequence of AML exosome-directed microRNA (miRNA) trafficking to HSPCs. Exosomes isolated from cultured AML or the plasma from mice bearing AML xenografts exhibited enrichment of miR-150 and miR-155...
2016: Science Signaling
Kenichi Miharada
Adult hematopoietic stem cells (HSCs) reside in bone marrow and are maintained in a dormant state within a special microenvironment, their so-called "niche". Detaching from the niche induces cell cycle progression, resulting in a reduction of the reconstitution capacity of HSCs. In contrast, fetal liver HSCs actively divide without losing their stem cell potentials. Thus, it has been unclear what types of cellular responses and metabolic changes occur in growing HSCs. We previously discovered that HSCs express relatively low levels of endoplasmic reticulum (ER) chaperone proteins governing protein folding, making HSCs vulnerable to an elevation of stress signals caused by accumulation of un-/misfolded proteins (ER stress) upon in vitro culture...
August 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
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