Disparate Effects of Interleukin 11 and Thrombopoietin on Megakaryocytopoiesis in Vitro

Taguchi, K; Saitoh, Minori; Arai, Yukinori; Momose, Kazuhiro; Ogawa, Y.; Yasuda, Shuhei; Miyata, Keiji

doi:10.1006/cyto.2001.0928

Cited by 5 publications

(5 citation statements)

References 24 publications

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“…We have made great effort toward determining optimal cytokine combinations that will promote megakaryocytic differentiation and maturation in the second culture stage. TPO is a major cytokine required for megakaryocytic lineage development, but TPO alone is not sufficient for obtaining large‐scale MK maturation []. In this study, IL‐6, in combination with the ST3L cytokine cocktail (combination of SCF, TPO, IL‐3, and LDL), was highly effective in stimulating megakaryopoiesis (Fig.…”

Section: Discussionmentioning

confidence: 79%

“…2A; supplemental online Table 1). IL‐11 also promotes the expansion and maturation of MKPs by modulating synergistic interactions with other early‐acting factors, such as IL‐3 and SCF [, ]. The addition of GM‐CSF to the ST3L6 + IL‐11 cocktail increased the expression of CD42b + mature megakaryocytes, perhaps also because of synergistic interactions with IL‐11.…”

Section: Discussionmentioning

confidence: 99%

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Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models

Guan

Qin

Zhang

et al. 2016

Stem Cells Translational Medicine

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Because of a lack of platelet supply and a U.S. Food and Drug Administration‐approved platelet growth factor, megakaryocytes have emerged as an effective substitute for alleviating thrombocytopenia. Here, we report the development of an efficient two‐stage culture system that is free of stroma, animal components, and genetic manipulations for the production of functional megakaryocytes from hematopoietic stem cells. Safety and functional studies were performed in murine and nonhuman primate models. One human cryopreserved cord blood CD34+ cell could be induced ex vivo to produce up to 1.0 × 104 megakaryocytes that included CD41a+ and CD42b+ cells at 82.4% ± 6.1% and 73.3% ± 8.5% (mean ± SD), respectively, yielding approximately 650‐fold higher cell numbers than reported previously. Induced human megakaryocytic cells were capable of engrafting and producing functional platelets in the murine xenotransplantation model. In the nonhuman primate model, transplantation of primate megakaryocytic progenitors increased platelet count nadir and enhanced hemostatic function with no adverse effects. In addition, primate platelets were released in vivo as early as 3 hours after transplantation with autologous or allogeneic mature megakaryocytes and lasted for more than 48 hours. These results strongly suggest that large‐scale induction of functional megakaryocytic cells is applicable for treating thrombocytopenic blood diseases in the clinic. Stem Cells Translational Medicine 2017;6:897–909

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models

Guan

Qin

Zhang

et al. 2016

Stem Cells Translational Medicine

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“…Supplementation with all three factors (IL-6, IL-11, and bFGF) together did not improve the outcome either (data not shown). Despite its modest effect, we decided to include IL-11 in our differentiation medium, since it was previously reported to enhance both the expansion and maturation of MKs 19, 20 . On the basis of these results, the MK differentiation medium used in our studies consists of Stemline II supplemented with TPO (50 ng/ml), SCF (20 ng/ml), and IL-11 (20 ng/ml), and is referred to as TSI medium.…”

Section: Resultsmentioning

confidence: 99%

Platelets generated from human embryonic stem cells are functional in vitro and in the microcirculation of living mice

Yin³

et al. 2011

Cell Res

159

166

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Platelets play an essential role in hemostasis and atherothrombosis. Owing to their short storage time, there is constant demand for this life-saving blood component. In this study, we report that it is feasible to generate functional megakaryocytes and platelets from human embryonic stem cells (hESCs) on a large scale. Differential-interference contrast and electron microscopy analyses showed that ultrastructural and morphological features of hESC-derived platelets were indistinguishable from those of normal blood platelets. In functional assays, hESC-derived platelets responded to thrombin stimulation, formed microaggregates, and facilitated clot formation/retraction in vitro. Live cell microscopy demonstrated that hESC-platelets formed lamellipodia and filopodia in response to thrombin activation, and tethered to each other as observed in normal blood. Using real-time intravital imaging with high-speed video microscopy, we have also shown that hESC-derived platelets contribute to developing thrombi at sites of laser-induced vascular injury in mice, providing the first evidence for in vivo functionality of hESC-derived platelets. These results represent an important step toward generating an unlimited supply of platelets for transfusion. Since platelets contain no genetic material, they are ideal candidates for early clinical translation involving human pluripotent stem cells.

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“…Among IL‐11 [9], PDGF [10], IL‐3 [11], IL‐6 [12], and SDF‐1α [8], which have all been accepted as megakaryocytopoiesis stimulators, IL‐11 was proven to be the most potent in enhancing megakaryocytic lineage expansion when it was used in combination with a cytokine cocktail of SCF/TPO/FL in our cultivation system (Table 1). Since IL‐11 acts directly on hematopoietic progenitor/stem cells and enhances megakaryocyte maturation as measured by a shift to higher ploidy values, its megakaryocytic progenitor expansion activities are predominantly a result of synergistic interaction with other early‐acting factors such as IL‐3 and SCF [16, 35, 38]. It therefore seemed reasonable to use IL‐11 in combination with SCF/TPO/FL for second phase, and in fact, the addition of PDGF, SDF‐1α, IL‐3, IL‐6, or TGF‐β ab to the SCF/TPO/FL/IL‐11 combination did not enhance the generation of megakaryocytic lineage cells.…”

Section: Discussionmentioning

confidence: 99%

Ex Vivo Large‐Scale Generation of Human Platelets from Cord Blood CD34 ⁺ Cells

et al. 2006

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Disparate Effects of Interleukin 11 and Thrombopoietin on Megakaryocytopoiesis in Vitro

Cited by 5 publications

References 24 publications

Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models

Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models

Platelets generated from human embryonic stem cells are functional in vitro and in the microcirculation of living mice

Ex Vivo Large‐Scale Generation of Human Platelets from Cord Blood CD34 ⁺ Cells

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Disparate Effects of Interleukin 11 and Thrombopoietin on Megakaryocytopoiesis in Vitro

Cited by 5 publications

References 24 publications

Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models

Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models

Platelets generated from human embryonic stem cells are functional in vitro and in the microcirculation of living mice

Ex Vivo Large‐Scale Generation of Human Platelets from Cord Blood CD34 + Cells

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Product

Resources

About

Ex Vivo Large‐Scale Generation of Human Platelets from Cord Blood CD34 ⁺ Cells