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G-CSF动员骨髓来源干细胞促进中风大鼠模型功能恢

9月20日circulation 电子版报道,CSF动员骨髓来源干细胞通过增强神经和血管再生促进中风大鼠模型功能恢复。该文作者用线拴法复制大鼠脑缺血再灌注模型,皮下注射G-CSF,核磁及行为学研究表明,G-CSF能够减小梗死面积,促进肢体功能改善,进一步研究表明,G-CSF能够动员骨髓造血干细胞进入血液循环,并向缺血区域募集,进一步分化成神经细胞和内皮细胞,促进血管和神经再生。为中风的治疗提供了新的策略,并为骨髓干细胞的可塑性提供了新的证据。
Published online before print September 20, 2004
Functional Recovery of Stroke Rats Induced by Granulocyte Colony-Stimulating Factor-Stimulated Stem Cells
Woei-Cherng Shyu MD, PhD, Shinn-Zong Lin MD, PhD, Hui-I Yang BSc, Yi-Shiuan Tzeng MS, Cheng-Yoong Pang PhD, Pao-Sheng Yen MD, and Hung Li PhD*
From the Department of Neurology, Neuro-Medical Scientific Center, Tzu-Chi Buddhist General Hospital, Tzu-Chi University, Hualien (W.-C.S., S.-Z.L., H.-I.Y., C.-Y.P., P.-S.Y.); Institute of Molecular Biology, Academia Sinica, Taipei (Y.-S.T., H.L.); and Institutes of Biochemistry, National Yang-Ming University, Taipei (H.L.), Taiwan.

* To whom correspondence should be addressed. E-mail: hungli@ccvax.sinica.edu.tw.

Background--Stroke is a leading cause of death and disability worldwide; however, no effective treatment currently exists.

Methods and Results--Rats receiving subcutaneous granulocyte colony-stimulating factor (G-CSF) showed less cerebral infarction, as evaluated by MRI, and improved motor performance after right middle cerebral artery ligation than vehicle-treated control rats. Subcutaneous administration of G-CSF enhanced the availability of circulating hematopoietic stem cells to the brain and their capacity for neurogenesis and angiogenesis in rats with cerebral ischemia.

Conclusions--G-CSF induced increases in bone marrow cell mobilization and targeting to the brain, reducing the volume of cerebral infarction and improving neural plasticity and vascularization.

Key words: granulocyte colony-stimulating factor • neuronal plasticity • stem cells, hematopoietic • stroke Stroke is a leading cause of death and disability worldwide,1 with no effective treatment that enhances stroke recovery. A potential strategy for the treatment of stroke is transplantation of bone marrow stem cells.2,3 These cells appear to enter through the blood-brain barrier and selectively migrate to the ischemic hemisphere of the damaged brain to improve neurological recovery.2,3 However, because cell transplantation requires surgical intervention, it is clinically desirable to explore less invasive therapeutic procedures.
Administration of granulocyte colony-stimulating factor(G-CSF) is known to mobilize hematopoietic stem cells(HSCs) from bone marrow into peripheral blood.4 Peripheralblood– derived HSCs have been used in place of bone marrow cells in transplantation for the regeneration of nonhematopoietic tissues such as skeletal muscle and heart.5 G-CSF has been used extensively for _10 years in the treatment of neutropenia, as well as for bone marrow reconstitution and stem cell mobilization.6
In stroke treatment through administration of stem cells, 2 main determinants are critical for the colonization and transdifferentiation of stem cells into a variety of tissues: (1) ischemic tissue damage and (2) the number of circulating stem cells available.5 Under ischemic conditions, circulating stem cells appear to selectively migrate to ischemic regions to support plasticity and functional recovery of damaged tissue.5 The expression of stromal cell– derived factor-1 (SDF-1) and its receptor CXCR4 after focal cerebral ischemia7 led us to speculate that this chemokine may also signal adhesion and migration of HSCs to ischemic tissue. On this basis, we hypothesized that cerebral ischemia enhances HSC plasticity and provides an environment that enhances differentiation of HSCs into original lineage cell types of the damaged organ, such as endothelial cells and neurons. In this study we used a rat model to test the hypothesis that chemokines could mobilize HSCs in a manner similar to that in which they target inflammatory cells in nonneuronal damaged tissues. A sufficient number of HSCs, mobilized by G-CSF, could then home in on cerebral ischemic injuries to promote neuronal repair and recovery of function; this would provide a basis for the development of a noninvasive autologous therapy for cerebral ischemia.
Methods
In Vivo Brain Ischemia/Reperfusion
Under anesthesia with chloral hydrate (0.4 g/kg), ligations of the right middle cerebral artery (MCA) and bilateral common carotid arteries (CCAs) were performed by methods described previously8 to induce cerebral infarction. Briefly, the bilateral CCAs were clamped with nontraumatic arterial clips. With the use of a surgical microscope, the right MCA was ligated with a 10-0 nylon suture. Cortical blood flow was measured continuously with a laser-Doppler flowmeter (PF-5010, Periflux system, Perimed A in anesthetized animals. After 90 minutes of ischemia, the suture on the MCA and arterial clips on CCAs were removed to allow reperfusion. During recovery from the anesthesia, body temperature was maintained at 37°C with a heat lamp.

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作者:admin@医学,生命科学    2010-12-27 05:14
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