Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis

Avecilla, Scott T.; Hattori, Koichi; Heissig, Beate; Tejada, Rafael; Liao, Francesca‐Fang; Shido, Koji; Jin, David; Dias, Sérgio; Zhang, Fan; Hartman, Travis; Hackett, Neil R.; Crystal, Ronald G.; Witte, Larry; Hicklin, Daniel J.; Bőhlen, Peter; Eaton, Dan; Lyden, David; Sauvage, Fredric De; Rafii, Shahin

doi:10.1038/nm973

Cited by 687 publications

(648 citation statements)

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“…Mounting evidence that cell-cell contacts, 22,23 ECM composition 19,20 and stiffness, 21 vascular shear stress, 24,25 pO2/pH, 51,52 soluble factor interactions, 22,53 and temperature 54 contribute to proPLT formation and PLT release have suggested that recapitulating key components of BM and blood vessel microenvironments within a three-dimensional microfluidic culture system is necessary to achieve clinically significant numbers of functional human PLTs. Our microfluidic bioreactor design expands control and resolution of the microenvironment, and has allowed us to drastically improve the time to PLT release (from 18 hours down to 2 hours) and more For personal use only.…”

Section: Discussionmentioning

confidence: 99%

“…This results in yields of 10 122 PLTs per CD34 1 cord blood-derived or embryonic stem cell-derived MK, 18 which are themselves of limited availability, constituting a significant bottleneck in the ex vivo production of a PLT transfusion unit. Although second-generation cell culture approaches have provided further insight into the physiological drivers of PLT release, they have been unable to recreate the entire BM microenvironment, exhibiting limited individual control of extracellular matrix (ECM) composition, 19,20 BM stiffness, 21 endothelial cell contacts, 22,23 and vascular shear stresses, 24,25 and have been unsuccessful in synchronizing proPLT production, resulting in nonuniform PLT release over a period of 6 to 8 days. 26 Moreover, the inability to reproduce the BM microenvironment ex vivo, and resolve physiological proPLT extension and release by high-resolution live-cell microscopy, has significantly hampered efforts to study the cytoskeletal and signaling mechanics of PLT production.…”

Section: Introductionmentioning

confidence: 99%

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Platelet bioreactor-on-a-chip

Thon

Mažutis

et al. 2014

Blood

180

201

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• We have developed a biomimetic microfluidic platelet bioreactor that recapitulates bone marrow and blood vessel microenvironments.• Application of shear stress in this bioreactor triggers physiological proplatelet production, and platelet release.Platelet transfusions total >2.17 million apheresis-equivalent units per year in the United States and are derived entirely from human donors, despite clinically significant immunogenicity, associated risk of sepsis, and inventory shortages due to high demand and 5-day shelf life. To take advantage of known physiological drivers of thrombopoiesis, we have developed a microfluidic human platelet bioreactor that recapitulates bone marrow stiffness, extracellular matrix composition, micro-channel size, hemodynamic vascular shear stress, and endothelial cell contacts, and it supports high-resolution live-cell microscopy and quantification of platelet production. Physiological shear stresses triggered proplatelet initiation, reproduced ex vivo bone marrow proplatelet production, and generated functional platelets. Modeling human bone marrow composition and hemodynamics in vitro obviates risks associated with platelet procurement and storage to help meet growing transfusion needs. (Blood. 2014;124(12):1857-1867) IntroductionAlthough platelets (PLTs) play critical roles in hemostasis, 1 angiogenesis, 2 and innate immunity, 3 PLT production remains poorly understood. Consequently, PLT units are derived entirely from human donors, despite serious clinical concerns owing to their immunogenicity and associated risk of sepsis. 4 More than 2.17 million apheresisequivalent PLT units are transfused yearly in the United States 5,6 at a cost of .$1 billion per year. Although demand for PLT transfusions has increased markedly in the past decade, a near-static pool of donors and a 5-day PLT unit shelf life resulting from bacterial contamination 7 and storage-related PLT deterioration, 8 have resulted in significant PLT shortages. 9 Furthermore, artificial platelet substitutes have failed to replace physiological platelet products. 10 An efficient, donorindependent PLT bioreactor capable of generating clinically significant numbers of functional human PLTs is necessary to obviate risks associated with PLT procurement and storage, and help meet growing transfusion needs. In vivo, megakaryocytes (MKs) PLT progenitors sit outside blood vessels in the bone marrow (BM) and extend long, branching cellular structures designated proPLTs into the circulation from which PLTs are released. 11-15 Nearly 100% of human adult MKs must produce ;10 3 PLTs each to account for circulating PLT counts. 16 Although functional human PLTs were first grown in vitro in 1995, 17 to date only ;10% of human MKs initiate proPLT production in culture. This results in yields of 10 122 PLTs per CD34 1 cord blood-derived or embryonic stem cell-derived MK, 18 which are themselves of limited availability, constituting a significant bottleneck in the ex vivo production of a PLT transfusion unit. Although second-generation c...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Platelet bioreactor-on-a-chip

Thon

Mažutis

et al. 2014

Blood

180

201

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“…An alternative vascular niche for HSCs composed of endothelial cells has recently been identified in both the bone marrow and the spleen [82,83]. Similar to the loss of the osteoblastic niche, depletion of endothelial cells in vivo also leads to diminished HSC activity and resulting hematopoietic failure [84]. Why then are there two distinct niches for the same HSC cells?…”

Section: Stem Cell Niche and Tumor Migrationmentioning

confidence: 99%

Beyond tumorigenesis: cancer stem cells in metastasis

et al. 2006

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“…42 Furthermore, adhesion of MK progenitors/precursors to bone marrow endothelial cells supports terminal MK differentiation and thrombopoiesis in the vascular niche. 43 Altogether, these observations suggest that KDR-induced adhesion in TF1-KDR cells is a physiological process, possibly favoring MK differentiation and maturation: accordingly, in vivo MK differentiation may be promoted by cell adhesion via KDR.…”

Section: Discussionmentioning

confidence: 79%