Role of fibrinolytic factors in the regulation of hematopoiesis

• Project/Area Number: 17591011
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Juntendo University
• Principal Investigator: BEATE Heissig Juntendo University, School of Medicine, Assistant Professor, 大学院医学研究科, 講師 (30372931)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000); Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
• Keywords: plasminogen / plasmin / plasminogen activator / matrix metalloproteinase / G-CSF / angiogenesis / mobilization / differentiation / プラスミノーゲンアクチベータ受容体 / マトリックスメタロプロテイナーゼ / 血管新生因子 / ケモカイン / トロンボポイエチン / プラスミノーゲンアクチベータ / 放射線 / 抗癌剤

Research Abstract

The overall question in the two-year study was to understand how proteases regulate bone marrow(BM)-derived hematopoietic and endothelial cell/stem cell mobilization. We focused on two proteolytic families, the fibrinolytic cascade and the matrix metalloproteinases (MMPs).
The urokinase plasminogen activator receptor (uPAR), a ligand for the serine proteinase urokinase plasminogen activator (uPA) is involved in cell movement and is part of the fibrinolytic cascade. Quantitative analysis of plasma levels of soluble uPAR (suPAR) in patient plasma samples after G-CSF treatment indicated that suPAR plasma levels correlated to leukocyte counts, but not to CD34+ stem cell counts in the peripheral blood. Therefore we concluded that suPAR is not a good marker for stem cell mobilization.
In another study we demonstrated that low-dose irradiation promotes endothelial progenitor cells (EPC)mobilization through MMP-9 mediated release of kit-ligand and VEGF release from mast cells.
We also were able to demonstrate that G-CSF-driven muscle tissue regeneration was partly mediated by the mobilization of BM-derived EPCs and vascular endothelial growth factor (VEGF) released from neutrophils.
In collaboration with the group of Dr. Raffi, we could show that CXCR4+/VEGF-receptor1+ BM-derived hemangiocytes promote cytokine-driven tissue regeneration.
Taken together, proteases play a role in the stem cell mobilization process. They are critical in shedding/releasing extracellular-or membrane-bound growth factors resulting in their bioavailability.

Research Products

• [Journal Article] Increased soluble urokinase plasminogen activator receptor (suPAR) serum levels after granulocyte-colony stimulating factor treatment do not predict successful progenitor cell mobilization in vivo (2006)
  • Author(s): Fiet Thomas
  • Journal Title: Blood 107 Pages: 3408-3409
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocyte. (2006)
  • Author(s): Jin David K.
  • Journal Title: Nature Medicine 12 Pages: 557-567
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 生体内血管新生および組織再生に関する新仮説-骨髄細胞動員を介した血管新生制御機構 (2006)
  • Author(s): 服部浩一
  • Journal Title: 実験医学 24 Pages: 2754-2760
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 骨髄血管ニッチの機能解析 (2006)
  • Author(s): 秋山晴代
  • Journal Title: 分子細胞治療 5 Pages: 124-129
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cytokine-mediated deployment of SDF-1 induces revascularisation through recruitment of CXCR4+ hemangiocytes. (2006)
  • Author(s): Jin DK, Shido K, Kopp HG, Petit I, Shmelkov SV, Young LM, Hooper ATA, Amano H, Avecilla ST, Heissig B, Hattori K, Zhang F, Hicklin DJ, Wu Y, Zhu Z, Salari H, Werb Z, Hackett NR, Crystal RG, Lyden D, Raffi S.
  • Journal Title: Nat.Med.(Epub)(Erratum) 12(5), 12(8)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased soluble urokinase plasminogen activator receptor (suPAR) serum levels after granulocyte colony-stimulating factor treatment do not predict successful progenitor cell mobilization in vivo. (2006)
  • Author(s): Fietz T, Hattori K, Thiel E, Heissig B.
  • Journal Title: Blood 107(8) Pages: 3408-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased soluble urokinase plasminogen activator receptor (suPAR) serum levels after granulocyte-colony stimulating factor treatment do mobilization in vivo. (2006)
  • Author(s): Fietz Thomas
  • Journal Title: Blood 107 Pages: 3408-3409
• [Journal Article] Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocyte. (2006)
  • Author(s): David K. Jin
  • Journal Title: Nature Medicine 12 Pages: 557-567
• [Journal Article] Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9 mediated progenitor cell mobilization. (2005)
  • Author(s): Heissig Beate
  • Journal Title: Journal of Experimental Medicine 202 Pages: 739-750
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. (2005)
  • Author(s): Ohki yuichi
  • Journal Title: FASEB J 19 Pages: 2005-2007
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A role for niches in hematopoietic cell development. (2005)
  • Author(s): Heissig Beate
  • Journal Title: Hematology 10 Pages: 247-253
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 骨髄幹細胞動員と組織再生のメカニズム. (2005)
  • Author(s): 佐藤弥生
  • Journal Title: 進歩する心臓研究 35 Pages: 5-12
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 造血幹細胞と血管新生. (2005)
  • Author(s): 大木勇一
  • Journal Title: 総合臨床 54 Pages: 98-106
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. (2005)
  • Author(s): Ohki Y, Heissig B, Sato Y, Akiyama H, Zhu Z, Hicklin DJ, Shimada K, Ogawa H, Daida H, Hattori K, Ohsaka A.
  • Journal Title: FASEB 19(14) Pages: 2005-7
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 「研究成果報告書概要(欧文)」より (2005)
  • Author(s): Heissig B, Rafii S, Akiyama H, Ohki Y, Sato Y, Rafael T, Zhu Z, Hicklin DJ, Okumura K, Ogawa H, Werb Z, Hattori K.
  • Journal Title: J.Exp.Med. 202(6) Pages: 739-50
• [Journal Article] 「研究成果報告書概要(欧文)」より (2005)
  • Author(s): Heissig B, Ohki Y, Sato Y, Rafii S, Werb Z, Hattori K.
  • Journal Title: Hematology 10(3) Pages: 247-53
• [Journal Article] Granulocyte-Colony Stimulating Factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. (2005)
  • Author(s): Ohki Yuichi
  • Journal Title: FASEB Journal 19 Pages: 2005-2007
• [Journal Article] A role for niches in hematopoietic cell development. (2005)
  • Author(s): heissig Beate
  • Journal Title: Hematology 10 Pages: 247-253
• [Journal Article] 造血幹細胞のmobilizationとhomingの制御機構 (2005)
  • Author(s): 服部浩一
  • Journal Title: 最新医学 60・8 Pages: 72-79
• [Journal Article] 骨髄幹細胞動員と組織再生のメカニズム (2005)
  • Author(s): 佐藤弥生
  • Journal Title: 進歩する心臓研究 35・1 Pages: 5-12
• [Journal Article] 造血幹細胞と血管新生 (2005)
  • Author(s): 大木勇一
  • Journal Title: 総合臨床 54・1 Pages: 98-106
• [Journal Article] Increased soluble urokinase plasminogen activator receptor (suPAR) serum levels after granulocyte-colony stimulating factor treatment do not predict successful progenitor cell mobilization in vivo.
  • Author(s): Fietz Thomas
  • Journal Title: Blood (印刷中)
• [Journal Article] 造血における骨髄血管ニッチの機能解析
  • Author(s): 秋山晴代
  • Journal Title: 分子細胞治療 (印刷中)