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      The extracellular matrix of hematopoietic stem cell niches

      a , * , 1 , a , 1 , b
      Advanced Drug Delivery Reviews
      Elsevier Science Publishers, B.V
      Extracellular matrix, Hematopoietic stem cell niche, Bone marrow, ADAM, a disintegrin and metalloproteinase, AML, acute myeloid leukemia, BM, bone marrow, CAMs, cell adhesion molecules, CAM-DR, cell adhesion mediated drug resistance, CAR, CXCL-12 abundant reticular, CFU, colony-forming-unit, CS, chondroitin sulfate, DDR, dimeric discoidin receptor, Del-1, developmentally-regulated endothelial cell locus-1, DG, dystroglycan, DS, dermatan sulfate, ECM, extracellular matrix, EGF, epidermal growth factor, FA, focal adhesion, FAK, focal adhesion kinase, FGF, fibroblast growth factor, FN I - III, fibronectin domain I - III, GAG, glycosaminoglycan, G-CSF, granulocyte colony stimulating factor, GM-CSF, granulocyte macrophage colony stimulating factor, HA, hyaluronic acid, HS, heparan sulfate, HSCs, hematopoietic stem cells, HSPCs, hematopoietic stem and progenitor cells, HSPGs, heparan-sulfated proteoglycans, HxB, hexabrachion, IL, interleukin, KS, keratan sulfate, KLS, c-KIT+ Lin- Sca+, LM, laminin, LAIR, leukocyte associated immunoglobuline like receptors, LOX, lysyl oxidase, LTR, long-term repopulating, MMPs, metalloproteinases, MSCs, mesenchymal stem/stromal cells, PEG, poly(ethylene glycol), RHAMM, receptor for hyaluronan mediated motility, Robo, roundabout, SCF, stem cell factor, SDF-1 also known as CXCL-12, stromal cell-derived factor 1, SLRPs, small leucine rich proteoglycans, TIMPs, tissue inhibitors of metalloproteinases, trOPN, thrombin-cleaved osteopontin, TLR, toll-like receptor, TGFβ, transforming growth factor β, VCAM, vascular cell adhesion molecule, VEGFR, vascular endothelial growth factor receptors

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          Graphical abstract


          • Comprehensive overview of different classes of ECM molecules in the HSC niche.

          • Overview of current knowledge on role of biophysics of the HSC niche.

          • Description of approaches to create artificial stem cell niches for several application.

          • Importance of considering ECM in drug development and testing.


          Hematopoietic stem cells (HSCs) are the life-long source of all types of blood cells. Their function is controlled by their direct microenvironment, the HSC niche in the bone marrow. Although the importance of the extracellular matrix (ECM) in the niche by orchestrating niche architecture and cellular function is widely acknowledged, it is still underexplored. In this review, we provide a comprehensive overview of the ECM in HSC niches. For this purpose, we first briefly outline HSC niche biology and then review the role of the different classes of ECM molecules in the niche one by one and how they are perceived by cells. Matrix remodeling and the emerging importance of biophysics in HSC niche function are discussed. Finally, the application of the current knowledge of ECM in the niche in form of artificial HSC niches for HSC expansion or targeted differentiation as well as drug testing is reviewed.

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          Most cited references559

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          Matrix elasticity directs stem cell lineage specification.

          Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. During the initial week in culture, reprogramming of these lineages is possible with addition of soluble induction factors, but after several weeks in culture, the cells commit to the lineage specified by matrix elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types. Inhibition of nonmuscle myosin II blocks all elasticity-directed lineage specification-without strongly perturbing many other aspects of cell function and shape. The results have significant implications for understanding physical effects of the in vivo microenvironment and also for therapeutic uses of stem cells.
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            Matrix crosslinking forces tumor progression by enhancing integrin signaling.

            Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening, and increased focal adhesions. Induction of collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibition of integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling, and induced the invasion of a premalignant epithelium. Consistently, reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy.
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              Mesenchymal and haematopoietic stem cells form a unique bone marrow niche.

              The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.

                Author and article information

                Adv Drug Deliv Rev
                Adv Drug Deliv Rev
                Advanced Drug Delivery Reviews
                Elsevier Science Publishers, B.V
                1 February 2022
                February 2022
                : 181
                : None
                [a ]Institute of Cell Biology and Biophysics, Leibniz University Hannover, Herrenhäuser Str. 2, 30419 Hannover, Germany
                [b ]Center for Medical Research, University Medical Clinic, Department II, Waldhörnlestraße 22, 72072 Tübingen, Germany
                Author notes

                These authors contributed equally to the presented work.

                S0169-409X(21)00462-2 114069
                © 2021 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                : 2 September 2021
                : 18 November 2021
                : 21 November 2021

                extracellular matrix,hematopoietic stem cell niche,bone marrow,adam, a disintegrin and metalloproteinase,aml, acute myeloid leukemia,bm, bone marrow,cams, cell adhesion molecules,cam-dr, cell adhesion mediated drug resistance,car, cxcl-12 abundant reticular,cfu, colony-forming-unit,cs, chondroitin sulfate,ddr, dimeric discoidin receptor,del-1, developmentally-regulated endothelial cell locus-1,dg, dystroglycan,ds, dermatan sulfate,ecm, extracellular matrix,egf, epidermal growth factor,fa, focal adhesion,fak, focal adhesion kinase,fgf, fibroblast growth factor,fn i - iii, fibronectin domain i - iii,gag, glycosaminoglycan,g-csf, granulocyte colony stimulating factor,gm-csf, granulocyte macrophage colony stimulating factor,ha, hyaluronic acid,hs, heparan sulfate,hscs, hematopoietic stem cells,hspcs, hematopoietic stem and progenitor cells,hspgs, heparan-sulfated proteoglycans,hxb, hexabrachion,il, interleukin,ks, keratan sulfate,kls, c-kit+ lin- sca+,lm, laminin,lair, leukocyte associated immunoglobuline like receptors,lox, lysyl oxidase,ltr, long-term repopulating,mmps, metalloproteinases,mscs, mesenchymal stem/stromal cells,peg, poly(ethylene glycol),rhamm, receptor for hyaluronan mediated motility,robo, roundabout,scf, stem cell factor,sdf-1 also known as cxcl-12, stromal cell-derived factor 1,slrps, small leucine rich proteoglycans,timps, tissue inhibitors of metalloproteinases,tropn, thrombin-cleaved osteopontin,tlr, toll-like receptor,tgfβ, transforming growth factor β,vcam, vascular cell adhesion molecule,vegfr, vascular endothelial growth factor receptors
                extracellular matrix, hematopoietic stem cell niche, bone marrow, adam, a disintegrin and metalloproteinase, aml, acute myeloid leukemia, bm, bone marrow, cams, cell adhesion molecules, cam-dr, cell adhesion mediated drug resistance, car, cxcl-12 abundant reticular, cfu, colony-forming-unit, cs, chondroitin sulfate, ddr, dimeric discoidin receptor, del-1, developmentally-regulated endothelial cell locus-1, dg, dystroglycan, ds, dermatan sulfate, ecm, extracellular matrix, egf, epidermal growth factor, fa, focal adhesion, fak, focal adhesion kinase, fgf, fibroblast growth factor, fn i - iii, fibronectin domain i - iii, gag, glycosaminoglycan, g-csf, granulocyte colony stimulating factor, gm-csf, granulocyte macrophage colony stimulating factor, ha, hyaluronic acid, hs, heparan sulfate, hscs, hematopoietic stem cells, hspcs, hematopoietic stem and progenitor cells, hspgs, heparan-sulfated proteoglycans, hxb, hexabrachion, il, interleukin, ks, keratan sulfate, kls, c-kit+ lin- sca+, lm, laminin, lair, leukocyte associated immunoglobuline like receptors, lox, lysyl oxidase, ltr, long-term repopulating, mmps, metalloproteinases, mscs, mesenchymal stem/stromal cells, peg, poly(ethylene glycol), rhamm, receptor for hyaluronan mediated motility, robo, roundabout, scf, stem cell factor, sdf-1 also known as cxcl-12, stromal cell-derived factor 1, slrps, small leucine rich proteoglycans, timps, tissue inhibitors of metalloproteinases, tropn, thrombin-cleaved osteopontin, tlr, toll-like receptor, tgfβ, transforming growth factor β, vcam, vascular cell adhesion molecule, vegfr, vascular endothelial growth factor receptors


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