2011 Fiscal Year Final Research Report
Stroke therapy using embryonic stem cells and bone marrow stromal cell-derived neuralstem cells
| Project/Area Number |
20390382
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Jun 京都大学, 再生医科学研究所, 教授 (10270779)
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| Project Period (FY) |
2008 – 2011
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| Keywords | 脳梗塞 / 神経幹細胞 / 骨髄間質細胞 / 胚性幹細胞 / 移植 |
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| Research Abstract |
Bone marrow stromal cells(MSCs) are an excellent source of cells for treating a variety of central nervous system diseases. We report the efficient induction of committed neural progenitor cells from rat and human MSCs(NS-MSCs) by introduction of cells with the intracellular domain of Notch-1 followed by growth in the free-floating culture system. To determine the therapeutic potential of NS-MSCs, cells were transplanted into the cortex and striatum in a rat model of focal cerebral ischemia. The survival, distribution, and integration of NS-MSCs in the host brain were very high, and at day 100, grafted NS-MSCs were positive for dopaminergic, glutamatergic, and gamma-amino butyric acid(GABA) ergic neuronal markers. They extended long neurites for nearly 6. 3 mm and many of these expressed synaptophysin. Significant behavioral recovery was also observed in limb-placing and water-maze tests.
To establish cell therapy for cerebral ischemia using embryonic stem(ES) cells, which have self-ren
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ewing and pluripotent capacities, we induced the differentiation of the neural progenitors from mouse ES cells using the serum-free suspension culture method and confirmed the expression of various basal ganglial neuronal markers and neurotransmitter-related markers both in vitro and in vivo, which was thought to be suitable for replacing damaged striatum after middle cerebral artery occlusion. We purified the progenitors expressing the neural progenitor marker Sox1 by fluorescence-activated cell sorting and Sox1-positive neural progenitors prevented tumor formation in ischemic brain for 2 months. We also analyzed survival and differentiation of transplanted cells and functional recovery from ischemic damage.
Induced pluripotent stem(iPS) cells possess the properties of self-renewal and pluripotency, similar to embryonic stem cells. They are a good candidate as a source of suitable cells for cell replacement therapy. In this study, we transplanted human iPS cell-derived neural progenitors into an ischemic mouse brain. Human iPS cells were differentiated into neuronal progenitors by serum-free culture of embryoid body-like aggregates(SFEBs). Donor cells were transplanted into the ischemic lateral striatum 1week after ischemia induction. Cells survived at the transplantation site, with migration of a proportion of cells along the external capsule and corpus callosum. Behavioral recovery was significantly enhanced in the transplanted group. Our results suggest that human iPS cell-derived neuronal progenitors survive and migrate in the ischemic brain, and contribute toward functional recovery vianeural circuit reconstitution.
Safe and efficient transplantation of embryonic stem(ES) cells to the brain requires that local inflammatory and immune responses to allogeneic grafts are inhibited. To investigate cytokines that affect graft cell survival and differentiation, we used stromal cell-derived inducing activity to induce the differentiation of neural progenitor cells(NPCs) from mouse ES cells and transplanted the NPCs into mouse brain. Examination of surrounding brain tissue revealed elevated expression levels of interleukin(IL)-1β, IL-4, and IL-6 in response to NPC transplantation. Among these, only IL-6 reduced neuronal differentiation and promoted glial differentiation in vitro. When we added anti-IL-6 receptor antibodies to NPCs during transplantation, this single and local blockade of IL-6 signaling reduced the accumulation of host-derived leukocytes, including microglia. Furthermore, it also promoted neuronal differentiation and reduced glial differentiation from the grafted NPCs to an extent similar to that with systemic and continuous administration of cyclosporine A. These results suggest that local administration of anti-IL-6 receptor antibodies with NPCs may promote neuronal differentiation during the treatment of neurological diseases with cell replacement therapy. Less
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[Journal Article] Transplantation of telencephalic neural progenitors induced from embryonic stem cells into subacute phase of focal cerebral ischemia2012
Author(s)
Fujimoto M, Hayashi H, Takagi Y, Hayase M, Marumo T, Gomi M, Nishimura M, Kataoka H, Takahashi J, Hashimoto N, Nozaki K, Miyamoto S.
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Journal Title
Lab Invest
Volume: 92(4)
Pages: 522-31
DOI
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[Journal Article] Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson's disease2012
Author(s)
Doi D, Morizane A, Kikuchi T, Onoe H, Hayashi T, Kawasaki T, Motono M, Sasai Y, Saiki H, Gomi M, Yoshikawa T, Hayashi H, Shinoyama M, Refaat MM, Suemori H, Miyamoto S, Takahashi J.
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Journal Title
Stem Cells
Volume: 30(5)
Pages: 935-45
DOI
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[Journal Article] Generate integration-free human iPS cells2011
Author(s)
Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, Hong H, Nakagawa M, Tanabe K, Tezuka K, Shibata T, Kunisada T, Takahashi M, Takahashi J, Saji H, Yamanaka S.
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Journal Title
Nat Methods
Volume: 8(5)
Pages: 409-12
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