Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord.
Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord.
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DOI：
10.1371/journal.pmed.0040039
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发表时间：
2007-02
期刊：
影响因子：
15.8
通讯作者：
Koliatsos VE
中科院分区：
文献类型：
--
作者：
Yan J;Xu L;Welsh AM;Hatfield G;Hazel T;Johe K;Koliatsos VE
目前尚无针对神经系统退行性和创伤性疾病的有效治疗方法。用神经移植物支持或替代受损的神经元，已经是实验治疗中的一种既定方法，最近随着神经和胚胎干衍生前体的添加作为胎儿组织取之不尽、用之不竭、自我繁殖的替代品，得到了新的活力。成人脊髓，即常见的破坏性损伤和运动神经元疾病的部位，一直是干细胞疗法特别具有挑战性的目标。在大多数情况下，神经干细胞（NSC）移植要么表现出分化不良，要么优先选择神经胶质细胞谱系。在本研究中，我们将单层生长的人胎儿脊髓中的神经干细胞移植到正常或受伤的成年裸鼠的腰髓中，并观察到这些细胞大规模分化为形成轴突和突触的神经元，并与宿主运动神经元建立广泛的接触。脊髓微环境似乎影响命运选择，位于中心的细胞呈现出主要的神经元路径，而位于软脑膜下的细胞则持续作为 NSC 或呈现星形胶质细胞表型。略少于十分之一的移植神经元分化为少突胶质细胞。病变的存在增加了白质中星形细胞表型的频率。 NSC 移植物可以在正常和受损的成人脊髓中显示出显着的神经元分化，并具有很好的融入宿主神经回路的潜力。鉴于其他实验室最近的类似发现，这里观察到的神经元分化程度与脊髓不利于神经元修复的概念存在争议。尽管仍然存在重大挑战，特别是在神经肌肉连接的建立方面，但创伤性和退行性疾病中脊髓回路的恢复可能比以前想象的更加现实。当来自人胎儿脊髓的神经干细胞被移植到正常或受伤的成年裸鼠的腰髓中时，发现了显着的神经元分化。每年，美国约有 11,000 人因脊髓损伤而瘫痪，其中许多是由道路交通事故造成的。发生这种瘫痪是因为脊髓是身体和大脑之间的主要通讯高速公路。来自皮肤和其他感觉器官的信息通过神经元束（传输和接收信息的神经系统细胞）沿着脊髓传输到大脑。然后，大脑将信息发送回脊髓，以控制运动、呼吸和其他身体功能。脊柱的骨头通常保护脊髓，但如果这些骨头断裂或脱臼，脊髓可能会被切断或压缩，从而中断信息流。脊髓顶部附近的损伤会使手臂和腿瘫痪（四肢瘫痪）；下部损伤仅使腿部瘫痪（截瘫）。脊髓损伤还会导致许多其他医疗问题，包括肠道和膀胱失去控制。尽管可以通过快速固定患者并使用药物减轻炎症来最大程度地减少脊髓损伤的有害影响，但受损的神经纤维永远不会再生。因此，脊髓损伤是永久性的。科学家目前正在寻找逆转脊髓损伤的方法。一种可能的方法是使用神经干细胞（NSC）替代受损的神经元。这些细胞可以从胚胎和成人神经系统的某些区域分离出来，能够发育成神经系统的所有特殊细胞类型。然而，由于大多数用神经干细胞移植修复脊髓损伤的尝试都没有成功，许多科学家认为脊髓的环境不适合神经再生。在这项研究中，研究人员研究了源自人类胎儿脊髓的神经干细胞移植到成年大鼠脊髓后会发生什么变化。研究人员将在培养皿中培养的人类神经干细胞注射到完整裸鼠（缺乏功能性免疫系统，因此不会破坏人类细胞）的脊髓中，以及脊髓在移植部位受损的裸鼠中。通过用与人类特异性蛋白质结合的抗体和识别 NSC、神经元或其他神经系统细胞特异性蛋白质的抗体对脊髓薄片进行染色来评估移植细胞的存活和命运。研究人员报告说，人类细胞在受伤和正常大鼠的成年脊髓中存活良好，并迁移到脊髓灰质（包含神经元细胞体）和白质（包含携带神经冲动的神经细胞的长延伸部分）。移植六个月后，灰质和白质中的人类细胞分别有 75% 和 60% 含有神经元特异性蛋白质，但脊髓周围膜中的细胞只有 10% 变成了神经元；其余的发育成星形胶质细胞（另一种神经系统细胞类型）或保留为干细胞。最后，许多源自人类的神经元产生了神经递质 GABA（一种在神经元之间传递信息的化学物质）并与宿主脊髓神经元建立了联系。这些发现表明，如果条件合适，人类 NSC 移植物毕竟可以在正常和受损的成人脊髓中发育成神经元（主要是产生 GABA 的神经元），并整合到现有的脊髓中。尽管这些动物实验表明 NSC 移植可能对脊柱损伤的人有帮助，但它们有一些重要的局限性。例如，这里使用的脊髓损伤是轻微的，与人类患者中看到的不同。这和裸鼠的使用可能减少了受损脊髓中的疤痕，这通常是神经再生的主要障碍。此外，研究人员没有测试 NSC 移植是否能改善脊髓损伤后的功能。然而，由于其他研究人员最近也报道称，神经干细胞可以在受损的成人脊髓中生长并发育成神经元，这些新结果进一步增强了人们对最终可能使用人类神经干细胞修复受损脊髓的希望。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/doi:10.1371/journal.pmed.0040039。美国国家神经疾病和中风研究所提供有关脊髓损伤和当前脊髓研究的信息 Spinal Research（英国慈善机构）提供有关脊髓损伤和修复的信息 美国国家脊髓损伤协会网站包含有关脊髓损伤的情况说明书 MedlinePlus 百科全书有有关脊髓损伤的页面和有关脊髓损伤的互动教程 国际干细胞研究学会提供有关包括 NSC 在内的各种干细胞的信息 美国国家人类神经干细胞资源提供有关人类神经干细胞的信息NSC，包括现任美国政府对干细胞研究的立场
Effective treatments for degenerative and traumatic diseases of the nervous system are not currently available. The support or replacement of injured neurons with neural grafts, already an established approach in experimental therapeutics, has been recently invigorated with the addition of neural and embryonic stem-derived precursors as inexhaustible, self-propagating alternatives to fetal tissues. The adult spinal cord, i.e., the site of common devastating injuries and motor neuron disease, has been an especially challenging target for stem cell therapies. In most cases, neural stem cell (NSC) transplants have shown either poor differentiation or a preferential choice of glial lineages. In the present investigation, we grafted NSCs from human fetal spinal cord grown in monolayer into the lumbar cord of normal or injured adult nude rats and observed large-scale differentiation of these cells into neurons that formed axons and synapses and established extensive contacts with host motor neurons. Spinal cord microenvironment appeared to influence fate choice, with centrally located cells taking on a predominant neuronal path, and cells located under the pia membrane persisting as NSCs or presenting with astrocytic phenotypes. Slightly fewer than one-tenth of grafted neurons differentiated into oligodendrocytes. The presence of lesions increased the frequency of astrocytic phenotypes in the white matter. NSC grafts can show substantial neuronal differentiation in the normal and injured adult spinal cord with good potential of integration into host neural circuits. In view of recent similar findings from other laboratories, the extent of neuronal differentiation observed here disputes the notion of a spinal cord that is constitutively unfavorable to neuronal repair. Restoration of spinal cord circuitry in traumatic and degenerative diseases may be more realistic than previously thought, although major challenges remain, especially with respect to the establishment of neuromuscular connections. When neural stem cells from human fetal spinal cord were grafted into the lumbar cord of normal or injured adult nude rats, substantial neuronal differentiation was found. Every year, spinal cord injuries, many caused by road traffic accidents, paralyze about 11,000 people in the US. This paralysis occurs because the spinal cord is the main communication highway between the body and the brain. Information from the skin and other sensory organs is transmitted to the brain along the spinal cord by bundles of neurons, nervous system cells that transmit and receive messages. The brain then sends information back down the spinal cord to control movement, breathing, and other bodily functions. The bones of the spine normally protect the spinal cord but, if these are broken or dislocated, the spinal cord can be cut or compressed, which interrupts the information flow. Damage near the top of the spinal cord can paralyze the arms and legs (tetraplegia); damage lower down paralyzes the legs only (paraplegia). Spinal cord injuries also cause many other medical problems, including the loss of bowel and bladder control. Although the deleterious effects of spinal cord injuries can be minimized by quickly immobilizing the patient and using drugs to reduce inflammation, the damaged nerve fibers never regrow. Consequently, spinal cord injury is permanent. Scientists are currently searching for ways to reverse spinal cord damage. One potential approach is to replace the damaged neurons using neural stem cells (NSCs). These cells, which can be isolated from embryos and from some areas of the adult nervous system, are able to develop into all the specialized cells types of the nervous system. However, because most attempts to repair spinal cord damage with NSC transplants have been unsuccessful, many scientists believe that the environment of the spinal cord is unsuitable for nerve regeneration. In this study, the researchers have investigated what happens to NSCs derived from the spinal cord of a human fetus after transplantation into the spinal cord of adult rats. The researchers injected human NSCs that they had grown in dishes into the spinal cord of intact nude rats (animals that lack a functioning immune system and so do not destroy human cells) and into nude rats whose spinal cord had been damaged at the transplantation site. The survival and fate of the transplanted cells was assessed by staining thin slices of spinal cord with an antibody that binds to a human-specific protein and with antibodies that recognize proteins specific to NSCs, neurons, or other nervous system cells. The researchers report that the human cells survived well in the adult spinal cord of the injured and normal rats and migrated into the gray matter of the spinal cord (which contains neuronal cell bodies) and into the white matter (which contains the long extensions of nerve cells that carry nerve impulses). 75% and 60% of the human cells in the gray and white matter, respectively, contained a neuron-specific protein six months after transplantation but only 10% of those in the membrane surrounding the spinal cord became neurons; the rest developed into astrocytes (another nervous system cell type) or remained as stem cells. Finally, many of the human-derived neurons made the neurotransmitter GABA (one of the chemicals that transfers messages between neurons) and made contacts with host spinal cord neurons. These findings suggest that human NSC grafts can, after all, develop into neurons (predominantly GABA-producing neurons) in normal and injured adult spinal cord and integrate into the existing spinal cord if the conditions are right. Although these animal experiments suggest that NSC transplants might help people with spinal injuries, they have some important limitations. For example, the spinal cord lesions used here are mild and unlike those seen in human patients. This and the use of nude rats might have reduced the scarring in the damaged spinal cord that is often a major barrier to nerve regeneration. Furthermore, the researchers did not test whether NSC transplants provide functional improvements after spinal cord injury. However, since other researchers have also recently reported that NSCs can grow and develop into neurons in injured adult spinal cord, these new results further strengthen hopes it might eventually be possible to use human NSCs to repair damaged spinal cords. Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040039. The US National Institute of Neurological Disorders and Stroke provides information on spinal cord injury and current spinal cord research Spinal Research (a UK charity) offers information on spinal cord injury and repair The US National Spinal Cord Injury Association Web site contains factsheets on spinal cord injuries MedlinePlus encyclopedia has pages on spinal cord trauma and interactive tutorials on spinal cord injury The International Society for Stem Cell Research offers information on all sorts of stem cells including NSCs The US National Human Neural Stem Cell Resource provides information on human NSCs, including the current US government's stance on stem cell research
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影响因子：
5.3
作者：
Han, SSW;Kang, DY;Fischer, I
通讯作者：
Fischer, I
影响因子：
64.8
作者：
Davies, SJA;Fitch, MT;Silver, J
通讯作者：
Silver, J
影响因子：
56.9
作者：
Fainzilber, M;Smit, AB;Geraerts, WPM
通讯作者：
Geraerts, WPM
DOI：
10.1073/pnas.0401103101
发表时间：
2004-05-04
影响因子：
11.1
作者：
Harper, JM;Krishnan, C;Kerr, DA
通讯作者：
Kerr, DA
影响因子：
5.3
作者：
Cao, QL;Howard, RM;Whittemore, SR
通讯作者：
Whittemore, SR