キャッチ
Stem cell regulation via dynamic interaction with the microenvironment: Implications for tissue regeneration
研究目的
Stem cells can differentiate into tissue-specific cells to repair damaged tissue. Hematopoietic stem cells are a rare population within the bone marrow, which actively maintain continuous production of all mature blood cells, including the immune system. The microenvironment modulates self-renewal, proliferation, and differentiation of hematopoietic stem cells enabling continuous production of all mature blood cells. The unique roles of stromal cells, chemokines, cytokines, adhesion molecules, and proteolytic enzymes, which regulate hematopoietic stem cells are currently being investigated. We aim to decipher the molecular mechanisms that govern hematopoietic stem cell mobilization, and how the microenvironment serves as a cell fate modulator. We seek to understand how hematopoietic cells are recruited into tissues, where they contribute to vessel formation (angiogenesis) of ischemic and malignant tissues.
研究内容
Past Research projects
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Stem cells are an attractive source of cells for tissue regeneration. Stem cells exist within specific niches in a quiescent state or are instructed to mobilize and proliferate following specific physiological stresses. We found that proteases, including matrix metalloproteinases (MMPs) and the serine proteinase plasmin are key factors in regulating e.g. growth factor supply within the bone marrow (BM) for hematopoietic stem cells (Heissig et al. Cell 2002; Heissig et al. Cell Stem Cells 2007). We have demonstrated that mobilizing factors not only promote cell mobilization into circulation, but also modulate cell incorporation into peripheral tissues (incl. ischemic tissues and cancer tissues), where new blood vessels are formed.
Current Research projects
Our research goal is to understand how hematopoietic stem cells and cancer cells are regulated. Our focus is on the role of the cellular microenvironment (I)-(II), on the development of techniques to obtain these rare stem cells (III), and on consideration of how we can use this knowledge in the light of the growing field of stem cell-based regenerative medicine with a focus on ischemic diseases (V).
(I) Investigation of factors derived from the microenvironment required for the maintenance, proliferation and differentiation of stem cells
Specialized niches in which hematopoietic stem cells (HSCs) reside control the balance between HSC quiescence and self-renewal. However, little is known about the extrinsic signals provided by the niche, nor how these niche signals regulate such a balance. Proteases, as a part of the microenvironment act as processing enzymes that perform highly selective and limited cleavage of specific substrates including growth factors and their receptors, cell adhesion molecules, cytokines, chemokines, apoptotic ligands and angiogenic factors. We aim to clarify the function of certain proteases in hematopoiesis, and to investigate possibility application of proteases for bone marrow remodeling.
(II) Identification of molecular mechanism of hematopoietic stem cell mobilization
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Adult bone marrow is a rich reservoir of hematopoietic and vascular stem and progenitor cells. Mobilization of hematopoietic stem and progenitor cells from the bone marrow into the circulation by administration of growth factors such as G-CSF is increasingly used clinically; but the mechanism is not fully understood. Accumulating evidences suggest that protease activation is an important step: proteases release cytokines or chemokines from the extracellular matrix, thereby modulating cell mobilization. We are studying the functional consequences of knockdown of various proteases for hematopoietic cell mobilization.
(III) Examine the mechanism how angiogenic factors regulate cancer growth and hematopoiesis
Angiogenic factors, like vascular endothelial growth factor, have been demonstrated to modulate blood cell formation (hematopoiesis). Hematopoietic cells, like myeloid cells present in the tumor microenvironment promote tumorigenesis by stimulating tumor cell growth and metastasis. The mechanism how these cells are recruited into tumor tissues of patients with malignant disorders is incompletely understood. Certain angiogenic factors have been implicated in hematopoietic cell migration. We are currently studying how certain recently discovered angiogeneic factors control tumor growth and modulate the tumor microenvironment by modulating the recruitment of tumor growth supporting hematopoietic cells.
(IV) Study the effect of proteolytic factors to improve vascular vessel development in ischemic diseases
Ischemia of the heart, brain and limbs is worldwide a leading cause of morbidity and mortality. Treatment with fibrinolytic factors can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. However, the underlying mechanism by which these factors improve ischemic tissue regeneration is not well understood. We are investigating the mechanism by which fibrionlytic factors modulate the angiogeneic response during ischemic tissue regeneration.
Contact us:
Beate Heissig, MD
Associate Professor
Frontier Research Initiative
Institute of Medical Science, University of Tokyo
heissig@ims.u-tokyo.ac.jp
Recruitment:
Highly motivated Japanese Ph.D students (2).
We can only accept foreign Ph.D student with grant support of at least 2 years.
Last modified June 2011
Selected Publications
I. Articles
1. Okaji Y, Tashiro Y, Gritli I, Nishida C, Sato A, Ueno Y, Del Canto Gnzalez S, Ohki-Koizumi M, Akiyama H, Nakauchi H, Nattori K, Heissig B. Plasminogen deficiency attenuates post-natal erythropoiesis in male C57BL/6 mice through decreased activity of the LH-testosterone axis. Exp. Hematology. (2011 Nov 3) Epub ahead of print.
2. Ishihara M, Nishida C, Tashiro Y, Gritli I, Rosenkvist J, Koizumi M, Okaji Y, Yamamoto R, Yagita H, Okumura K, Nishikori M, Wanaka K, Tsuda Y, Okada Y, Nakauchi H, Heissig B, Hattori K. Plasmin inhibitor reduces T-cell lymphoid tumor growth by suppressing matrix metalloproteinase-9-dependent CD11b(+)/F4/80(+) myeloid cell recruitment. Leukemia. doi: 10.1038/leu. 2011.203.(2011 Sep 20) Epub ahead of print.
3. Piao JH, Hasegawa M. Heissig B, Hattori K, Takeda K, Iwakura Y, Okumura K, Inohara N, Nakano H. Tumor necrosis factor receptor-associated factor (Traf)2 controls homeostasis of the colon to prevent spontaneous development of murine inflammatory bowel disease. J Biol Chem 286 (20), 17879-88 (2011 May 20) Epub 2011 May 10.
4. Aoki N, Yokoyama R, Asai N, Ohki M, Ohki Y, Kuzubata K, Heissig B, Hattori K, Nakagawa Y, and Matsuda T. Adipocyte-derived microvesicles are associated with multiple angiogenic factors and induce angiogenesis in Vivo and in Vitro. Endocrinology 151(6), 2567-76 (2010 Jun)
5. Ohki M, Ohki Y, Ishihara M, Nishida C, Tashiro Y, Akiyama H, Komiyama H, Lund LR, Atsumi Nitta A, Yamada, K, Zhu Z, Ogawa, H, Yagita H, Okumura K, Nakauchi H, Werb Z, Hattori K, Heissig B. Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneneration. Blood 115 (21), 4302-12 (2010 May 27) Epub 2010 Jan 28.
6. Heissig B, Nishida C, Tashiro Y, Sato Y, Ishihara M, Ohki M, Gritli I, Rosenkvist J, Hattori K. Role of neutrophil-derived matrix metalloproteinase-9 in tissue regeneration. Histology and Histopathology 25 (6), 765-70 (2010 Jun).
7. Sato Y, Ohki Y, Akiyama H, Rosenkvist J, Gritli I, Okumura K, Ogawa H, Daida H, Heissig B, Hattori K, Ohsaka A. Targeted deletion of matrix metalloproteinase-9 reduces neutrophil accumulation during G-CSF-induced neoangiogenesis. Cytometry Research 19 (2), 53-62 (2009).
8. Heissig B, Ohki M, Ishihara M, Tashiro Y, Nishida C, Gritli I, Rosenkvist J, Hattori K. Contributions of the fibrinolytic pathway to hematopoietic regeneration. J. Cell Physiol. 221 (3), 521-5 (2009 Dec).
9. Kerbel RS, Benezra R, Lyden DC, Hattori K, Heissig B, Nolan DJ, Mittal V, Shaked Y, Dias S, Bertolini F, Rafii S. Endothelial progenitor cells are cellular hubs essential for neoangiogenesis of certain aggressive adenocarcinomas and metastatic transition but not adenomas. Proc. Natl. Acad. Sci. USA 105 (34), E54-E55 (2008 Aug 26) Epub 2008 Aug 20.
10. Nishikii H, Eto K, Tamura N, Hattori K, Heissig B, Kanaji T, Sawaguchi A, Goto S, Ware J, Nakauchi H. Metalloproteinase regulation improves in vitro generation of efficacious platelets from embryonic stem cells. J. Exp. Med. 205 (8), 1917-27 (2008 Aug 4) Epub 2008 Jul 28.
11. Hattori K, Ishihara M, Heissig B. Bone Marrow-derived cells contribute to niche formation in cancer progression. Clin. Calc. 18 (4), 420-27 (2008 Apr).
12. Heissig B, Lund LR, Akiyama H, Ohki M, Morita Y, Rømer J, Nakauchi H, Okumura K, Ogawa H, Werb Z, Danø K, Hattori K. The plasminogen fibrinogen pathway is required for hematopoietic regeneration. Cell Stem Cell 1, 658–670 (2007).
13. 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, Rafii. S. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nature Med. 12, 557-97 (2006).
14. Heissig B, Rafii S, Akiyama H, Ohki Y, Sato Y, Rafael T, Zhu Z, Hicklin DJ, Okumura K, Werb Z, Hattori K. Low-dose irradiation promotes tissue revascularisation through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. J. Exp. Med. 202, 739-50 (2005).
15. Ohki Y, Heissig B, Sato Y, Akiyama H, Zhu Z, Hicklin DJ, Shimada K, Ogawa H, Daida H, Hattori K, Ohsaka A. Granulocyte-Colony Stimulating Factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. FASEB J 19(14), 2005-7 (2005).
16. Heissig B, Avecilla ST, Hattori K, Tejada R, Liao F, Shido K, Jin DK, Dias S, Zhang F, Hartman TE, Hackett NR, Crystal RG, Witte L, Hicklin DJ, Bohlen P, Eaton D, Lyden D, de Sauvage F, Rafii S. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nature Med. 10, 64-71 (2004).
17. Heissig B,* Hattori K,* Dias S, Ferris B, Friedrich M, Ferris B, Hackett NR, Lyden D, Crystal RG, Besmer P, Moore MAS, Werb Z, Rafii S. Recruitment of Stem and Progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625-637 (2002).
18. Heissig B,* Hattori K,* Wu Y, Tejada R, Hicklin D, Zhu Z, Bohlen P, Witte L, Ferris B, Dias S, Hendriks J, Hacket NR, Crystal RG, Moore MAS, Werb Z, Lyden D, Rafii S. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone marrow microenvironment. Nature Med. 8, 841-849 (2002).
19. Hattori K, Heissig B, Tashiro K, Honjo T, Tateno M, Hackett DJ, Quitoriano MS, Crystal RG, Rafii S, MAS Moore. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 97, 3354-3360 (2001).
20. Moore MA, Hattori K, Heissig B, Shieh S, Crystal RG, Rafii S. Mobilization of endothelial and hematopoietic stem and progenitor cells by adneovector-mediated elevation of serum levels of SDF-1, VEGF and angiopoietin-1. Ann. N. Y. Acad. Sci. 938, 36-45 (2001).
21. Dias S*, Hattori K*, Heissig B, Zhu Z, Wu Y, Witte L, Hicklin DJ, Tateno M, Bohlen P, Moore MAS, Rafii S. Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. PNAS 98, 10857-10862 (2001).
22. Heissig B, Pasternak G, Schwerdtfeger G, Hehlmann R. CD14+ peripheral blood mononuclear cells from chronic myelogenous leukemia and normal donors are inhibitory to short- and long-term cultured colony-forming cells. Leuk. Research 24, 217-31 (2000).
* The authors contributed equally to this work.
II. Reviews
1. Heissig B, Nishida C, Tashiro Y, Sato Y, Ishihara M, Ohki M, Gritli I, Rosenkvist J, Hattori K. Role of neutrophil-derived matrix metalloproteinase-9 in tissue regeneration. Histology and Histopathology, 25(6), 765-70, 2010.
2. Heissig B, Ohki M, Ishihara M, Tashiro Y, Nishida C, Gritli I, Rosenkvist J, Hattori K. Contributions of the fibrinolytic pathway to hematopoietic regeneration. J Cell Physiol. 221(3), 521-5 (2009).
3. Heissig B, Ohki Y, Sato Y, Rafii S, Werb Z, Hattori K. A role for niches in hematopoietic cell development. Hematology 10(3), 247-53 (2005).
4. Heissig B, Werb Z, Rafii S, Hattori K. Role of c-kit/kit ligand signaling in regulating vasculogenesis. Thrombosis and Haemostasis 90 (4), 570-6 (2003).
5. Heissig B, Hattori K, Friedrich M, Rafii S, Werb Z. Angiogenesis: vascular remodeling of the extracellular matrix involves metalloproteinases. Curr. Opin. Hematol. 10, 136-141 (2003).
Group Members (including member's of the group of Dr. Hattori)
Beate Heissig
Associate Professor
Koichi Hattori
Associate Professor
Yoko Ueno
Technician
Kaori Kusubata
Researcher
Chiemi Nishida
Ph.D Student
Makiko Ohki
Ph.D Student
Ismael Gritli
Ph.D Student
Yoshihiko Tashiro
Ph.D Student
Hiroshi Shimazu
Ph.D Student
Yayoi Sato
Visiting Researcher
Hiromitsu Komiyama
Visiting Researcher
Frontier Research Initiative
The Institute of Medical Science, The University of Tokyo
Frontier Research Initiative
Associate Professor
heissig@ims.u-tokyo.ac.jp