内源性神经干细胞修复中枢神经系统损伤的策略

神经干细胞（NSCs）具有增殖、迁移及分化的特性。动员内源性NSCs已成为修复中枢神经系统（CNS）损伤的一条新策略。近年来不少研究表明,营养因子、细胞因子、高压氧、中医药、丰富环境和康复训练等措施可以促进内源性NSCs动员,而且利用具有NSCs特性的神经细胞同样有利于促进CNS损伤的修复。     

神经干细胞在修复脊髓损伤中的应用

成年中枢神经系统损伤后其自身的修复能力是有限的，死亡的神经元不能由中枢神经系统自身产生新的神经元或邻近的神经元来替换。然而，近年来神经干细胞(neural stem cells，NSCs)的研究已改变了这些观点，现已发现中枢神经系统的一些区域终生存在产生新神经元的能力，通过移植神经干细胞来修复损伤的神经系统是有可能的。本文就神经干细胞的特性及其在修复脊髓损伤方面的作用作一简述。     

骨髓基质干细胞移植在脊髓损伤中的应用

1．概述 脊髓损伤是一种严重的中枢神经系统的创伤性疾病，病情严重的患者往往面临终生瘫痪。只有损伤较轻的患者才有机会恢复脊髓功能，多数患者的治疗效果很不理想，患者失去损伤节段以下的运动和感觉能力，严重影响患者的生活质量，给家庭和社会带来沉重负担。近年来细胞移植成为脊髓损伤治疗的研究热点，尤其是骨髓基质干细胞能够取材于成人自身的骨髓，避免了胚胎干细胞和神经干细胞所带来的伦理学和免疫排斥问题，并且容易增殖，这些优点使得骨髓基质干细胞成为极有前景的移植材料。     

中枢神经系统干细胞研究进展

近年来，中枢神经系统干细胞的研究方法和其在临床应用方面的价值日益成为神经干细胞研究的焦点，本文对于神经干细胞的发现，最新的神经干细胞研究技术以及神经干细胞在中枢神经系统退变性疾病，缺血损伤和肿瘤治疗等方面的研究进展作一概述。     

神经干细胞与脊髓损伤的修复研究现状与展望

神经干细胞在哺乳动物中枢神经许多区域存在,已经从胚胎、胎儿和成人脑组织的不同部位,包 括海马、脑室/室管膜以及从皮质分离出来,能够在体外或体内扩增、分化为神经元和神经胶质。利用神经干 细胞进行细胞替代治疗和基因治疗有很好的临床应用前景,为治疗和修复脊髓损伤带来了希望。移植神经干 细胞或它们的分化产物至宿主脑,继而分化为内生干细胞是很多神经退行性变疾病的潜在治疗方法。     

中枢神经系统损伤后神经细胞及nestin蛋白的变化

神经干细胞是近十多年来在神经生物学领域的重大发现，并成为该领域的热点之一。神经干细胞在成年哺乳类动物中枢神经系统中的发现为神经系统损伤及退行性疾病的治疗和康复带来新的希望。目前，用异体胎脑或神经干细胞移植进行神经替代治疗的研究已取得一定成果。然而，中枢神经损伤后对自体内源性神经干细胞活动及其物nestin蛋白的研究也有望在神经替代方面取得突破。本文就中枢神经系统损伤后神经干细胞及nestin蛋白的变化做一回顾。     

中药调控神经干细胞促进中枢神经系统神经再生与修复的研究进展

传统观点认为，中枢神经系统（central nervous system，CNS）在损伤后缺乏自身修复能力。1992年，Reynolds和Weiss从成年小鼠纹状体中分离出了能在体外不断分裂增殖、具有多种分化潜能的神经干细胞（neural stem cell，NSC），这就对CNS发育成熟后不可能再生的理论提出了挑战，同时也为神经系统损伤修复及功能重建带来了希望。正常情况下CNS内NSC的数目较少，并且大部分新发生的神经细胞在短期内会死亡，所以中枢神经系统内神经再生的发生频率很低。     

中枢神经系统的多能干细胞

StemcellsinthecentralNervousSystemMckayR80年代末．通过高体和在体实验证实在脊椎动物胚胎的中枢神经系统中存在多能干细胞，它们能分化形成神经元和胶质细胞（包括星形胶质细胞和少突胶质细胞）。1992年Reynolds从成年小鼠大脑中分离出多能干细胞进行体外培养。现已证实在体外培养条件下，某些促分裂因子如表皮生长因子（EGF）、碱性成纤维细胞生长因子（bFGF）等能促进中枢神经系统的多能干细胞增殖．其增殖速度足以解释发育过程中大脑细胞的数量变化。另外，转化生长因子-β（TGF-β）家族能影响中枢神经系统多能干细胞的节段特…     

神经烯醇化酶与中枢神经系统发育、损伤修复的研究进展

神经烯醇化酶（NSE）作为神经元发育、重塑的特异性标志物,在中枢神经系统发育和损伤修复过程中呈时空性表达分布。损伤后NSE的改变可以反映病理变化,通过调节NSE水平可以达到损伤后的修复效果,对神经系统的损伤修复有重要意义。本文中我们就NSE的分子结构、表达调控、生物学功能及其与中枢神经系统发育、损伤修复关系进行综述。     

成年哺乳类动物中枢神经系统内的干细胞

<正> 1991年,加拿大神经科学家B·A·Reynolds和S.Weiss根据表皮生长因子(EGF)对胚胎脑发育的作用及成年脑内广泛存在的EGF和EGFR免疫化学反应,开展了有意义的实验。他们取3～18个月龄的成年小鼠纹状体,酶解后种植于无血清培养基中。加入每毫升20ng浓度的EGF培养。2天后,每个培养皿中1000个培养细胞有15±2个存活下来。并出现分裂增殖现象。继续培养2～3天后,形成了增殖细胞团(a sphere of proliferating     

神经前体细胞不是胚胎干细胞向胰岛素分泌细胞分化的必经途径

探讨胚胎干细胞向胰岛素分泌细胞分化的途径,对胰腺组织工程的临床运用有重要意义。将胚胎干细胞在有小鼠胚胎成纤维细胞饲养层和白血病抑制因子的条件下培养扩增后,再将扩增后的胚胎干细胞不经过神经前体细胞阶段直接诱导为胰岛素分泌细胞,并与传统的多阶段诱导(经过神经前体细胞阶段)进行比较。结果发现,胚胎干细胞脱离饲养层细胞后,经过9~10d的分化诱导,可以分化为具有胰岛β-细胞特征的胰岛素分泌细胞。与传统的多阶段诱导方法相比,诱导过程简化,诱导时间缩短,所得到的胰岛素分泌细胞数量无明显差异。说明胚胎干细胞向胰岛素分泌细胞分化存在多条途径。神经前体细胞阶段不是胚胎干细胞向胰岛素分泌细胞分化的必须途径。用传统的多阶段分化诱导法和直接诱导法都可以将胚胎干细胞诱导成胰岛素分泌细胞。     

Distinctive Infectious Complications in Patients with Central Nervous System Lymphoma Undergoing Thiotepa,Busulfan, and Cyclophosphamide-conditioned Autologous Stem Cell Transplantation

We investigated the incidence of viral, fungal, bacterial, and parasitic infections observed in 57 patients with central nervous system lymphoma after thiotepa, busulfan, and cyclophosphamide-conditioned autologous stem cell transplantation (TBC-ASCT) and 79 patients with systemic non-Hodgkin lymphoma after traditional carmustine, etoposide, cytarabine, and melphalan–conditioned ASCT (BEAM-ASCT). Twenty of 57 (35%) TBC-ASCT patients had detectable viremia with human herpesvirus 6, cytomegalovirus, adenovirus, or BK virus, versus 9 of 79 (11%) BEAM-ASCT patients. Eight TBC-ASCT patients had clinically relevant viral infections (4 human herpesvirus 6, 2 cytomegalovirus, 1 adenovirus, 2 BK virus), versus 0 in the BEAM-ASCT group. Four TBC-ASCT patients suffered infections from either a fungal or parasitic pathogen versus 1 BEAM-ASCT patient. TBC was associated with greater risk of viral reactivation compared with BEAM, independent of other factors (hazard ratio, 4.42; 95% confidence interval, 1.9 to 11.3; P?<?.001). Prolonged lymphopenia and steroid use in the peri- and post-ASCT period did not explain these observed differences. The pathogenesis of these unusual infections in TBC-ASCT patients remains incompletely understood, and may involve more potent immune suppression with TBC conditioning. Clinicians should be aware of these differences in infection risk in TBC-ASCT patients, which more closely parallel those seen in allogenic hematopoietic cell transplantation recipients. New prophylactic approaches to help minimize these infections should be considered in this population.     

Central Nervous System Relapse in Adults with Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS relapse after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. In a 3-center retrospective analysis, we reviewed the data for 457 adult patients with ALL who received a first allogeneic HSCT in first or second complete remission (CR). All patients received CNS prophylaxis as part of their upfront therapy for ALL, but post-transplantation CNS prophylaxis practice varied by institution and was administered to 48% of the patients. Eighteen patients (4%) developed CNS relapse after HSCT (isolated CNS relapse, n = 8; combined bone marrow and CNS relapse, n = 10). Patients with a previous history of CNS involvement with leukemia had a significantly higher rate for CNS relapse (P = .002), and pretransplantation CNS involvement was the only risk factor for post-transplantation CNS relapse found in this study. We failed to find a significant effect of post-transplantation CNS prophylaxis to prevent relapse after transplantation. Furthermore, no benefit for post-transplantation CNS prophylaxis could be detected when a subgroup analysis of patients with (P = .10) and without previous CNS involvement (P = .52) was performed. Finally, we could not find any significant effect for intensity of the transplantation conditioning regimen on CNS relapse after HSCT. In conclusion, CNS relapse is an uncommon event after HSCT for patients with ALL in CR1 or CR2, but with higher risk among patients with CNS involvement before transplantation. Furthermore, neither the use of post-HSCT CNS prophylaxis nor the intensity of the HSCT conditioning regimen made a significant difference in the rate of post-HSCT CNS relapse.     

A Comprehensive Assessment of Toxicities in Patients with Central Nervous System Lymphoma Undergoing Autologous Stem Cell Transplantation Using Thiotepa,Busulfan, and Cyclophosphamide Conditioning

High-dose therapy and autologous stem cell transplantation (ASCT) with thiotepa, busulfan, and cyclophosphamide (TBC) conditioning has emerged as an effective postinduction treatment strategy for patients with primary central nervous system lymphoma (PCNSL) or secondary central nervous system lymphoma (SCNSL), but it is associated with considerable toxicity and transplantation-related mortality (TRM) in the modern era. Forty-three adult patients with chemosensitive PCNSL or SCNSL underwent TBC-conditioned ASCT between 2006 and 2015. Twenty-eight of these patients received pharmacokinetically (PK)-targeted busulfan dosing. The median number of clinically relevant individual grade?≥3 nonhematologic toxicities per patient was 5. We found no association between pretransplantation patient characteristics and the presence of more than 5 grade?≥3 nonhematologic toxicities. Patients with elevated first-dose busulfan area under the curve values did not experience more toxicity. Paradoxically, patients treated with more than 2 regimens before undergoing ASCT had lower first-dose busulfan AUC values. With a median follow-up among survivors of 20 months, 1-year progression-free survival (PFS) and overall survival (OS) from the time of ASCT were 83% and 87%, respectively. Although this study reaffirms the favorable PFS and OS associated with TBC-conditioned ASCT for PCNSL or SCNSL, this treatment strategy carries a large toxicity burden.     

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients with Central Nervous System Involvement

Central nervous system (CNS) involvement in adult acute myeloid leukemia (AML) is rare and associated with poor outcomes. Therefore, CNS involvement in AML is an indicator for allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the impact of CNS involvement in AML on the outcome of allo-HSCT remains unclear. We performed a large-scale nationwide retrospective analysis to elucidate the outcomes of allo-HSCT on AML with CNS involvement (CNS+AML). Clinical data were collected from a registry database of the Japan Society for Hematopoietic Cell Transplantation. CNS involvement was defined as the infiltration of leukemia cells into the CNS or myeloid sarcoma in the CNS identified at any time from diagnosis to transplantation. One hundred fifty-seven patients with CNS+AML underwent allo-HSCT between 2006 and 2011. The estimated overall survival, cumulative incidence of relapse and nonrelapse mortality at 2 years for CNS+AML (51.2%, 30.2%, and 14.5%, respectively) were comparable with those for AML without CNS involvement (48.6%, 27.4%, and 22.0%, respectively). Univariate and multivariate analyses indicated that the development of chronic graft-versus-host disease, disease status, and cytogenetic risk category were independent prognostic factors for overall survival for CNS+AML. These results suggest that allo-HSCT may improve outcomes in patients with CNS+AML.     

Augmenting Total Body Irradiation with a Cranial Boost before Stem Cell Transplantation Protects Against Post-Transplant Central Nervous System Relapse in Acute Lymphoblastic Leukemia

The purpose of this study was to determine the effect of a pretransplant cranial boost (CB) on post-transplant central nervous system (CNS) relapse and survival in acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) using a total body irradiation (TBI)-containing preparation regimen. Two hundred thirteen ALL patients were treated consecutively at our institution with allogeneic HSCT. Conditioning included TBI (1320?cGy in 8 fractions given twice daily) and cyclophosphamide (120?mg/kg) with or without fludarabine (75?mg/m²). Patients were divided into 4 groups based on history of CNS disease and whether a CB was given. Of the 160 patients with no history of CNS disease, none received a CB (CNS?/CB?). Of the 53 patients with prior CNS disease, 41 had not received prior cranial irradiation. Thirty of these 41 received a CB of 900 to 1000?cGy in 5 daily fractions (CNS+/CB+), whereas the other 11 did not receive a CB because of physician preference (CNS+/CB?). The remaining 12 patients with prior CNS involvement had previously received cranial irradiation and thus were not candidates for a CB (CNS?+?PriorRT). Two-year CNS relapse risk, overall survival (OS), and disease-free survival (DFS) were calculated using Kaplan-Meier analysis. Seven patients experienced post-transplant CNS relapse: 4 in the CNS?/CB? group, 2 in the CNS+/CB? group, and 1 in the CNS?+?PriorRT group. None of the 30 patients who received a CB relapsed in the CNS. Two-year CNS relapse risk was 0% in the CNS+/CB+ group compared with 21% (95% CI, 0% to 45%) in the CNS+/CB? group (P?=?.03). Two-year OS and DFS did not differ between the groups. In conclusion, among ALL patients with prior CNS leukemia, there was a trend toward a reduced risk of post-transplant CNS relapse in patients who received a CB. However, the addition of a CB did not appear to have an impact on OS or DFS.     

胚体培养对小鼠ES细胞定向神经分化的影响研究

为了研究胚胎干细胞（ES细胞）的定向诱导分化过程中胚体的形成对其后分化的影响，通过悬滴培养、悬浮培养及两者结合的方法得到2～4d的胚体（EBs），利用全反视黄酸（RA）对其处理4d后，进行免疫细胞化学和兴奋性功能的检测，观察比较了不同培养方式和不同培养时间下EBs分化出来的神经细胞所占的比例。结果表明，用单纯悬浮3d或悬滴3d转悬浮1d的培养方法得到的胚体其神经分化的比例较高，这对进一步阐明胚胎干细胞自身内部调控诱导分化的机制有一定的参考意义。     

中枢神经系统氧感受神经元的研究进展

中枢神经系统内从丘脑到延髓的整个脑干区域分布着许多氧化学感受器,并组成了一个复杂的感受氧气的网络,它们在氧浓度变化的过程中对心血管与呼吸系统起着重要的调节作用.目前关于中枢氧感受器化学传递过程的细胞机制中,仅有颈动脉体血管球细胞和肺血管平滑肌细胞的保护机制,而中枢性氧感受神经元需要何种的离子通道和氧感受器传导缺氧的机制目前还不很清楚,本文主要对此方面目前的相关研究作简要综述.     

胚胎干细胞用于药物及其他化合物筛选的研究进展

胚胎干细胞 (Em bryonic stem cell,ES cell)用于药物及其他化合物的体外筛选 ,称为胚胎干细胞体外测试 (Embryonic stem cell test,EST) ,通过 EST可以把药物等化合物分为三类 :无毒性、弱毒性和强毒性。与其他方法相比 ,EST具有很大优点 :(1)无须牺牲大量怀孕动物。(2 )不用担心对动物或人体的巨大副作用。(3)由于胚胎干细胞在体外分化成多种细胞的潜能 ,EST可用于分化过程中药物或其他化合物对发育过程造成的毒理学研究。(4)可与计算机等分析方法结合 ,因而具有更高的准确率和敏感性。 (5 )可以进行分子水平的定量研究。这些都使得EST在药物筛选中显示出巨大的发展前景。本文综述了 EST的发展、研究方法、现状及其展望。     

ASBMT Statement on Routine Prophylaxis for Central Nervous System Recurrence of Acute Lymphoblastic Leukemia following Allogeneic Hematopoietic Cell Transplantation

Hematologic malignancies treated with allogeneic hematopoietic cell transplantation (allo-HCT) have a variable incidence of post-transplantation central nervous system (CNS) relapse, with acute lymphoblastic leukemia (ALL) representing the most common disease histology. Although data supporting post-transplantation CNS prophylaxis for ALL in the pre-CNS penetrant systemic therapy era established this as standard practice, controversy exists regarding the role of post-transplantation CNS prophylaxis in the contemporary era. Here we review the most relevant (albeit exclusively retrospective) literature to date on the role of post-transplantation CNS prophylaxis in ALL. Given the paucity of data supporting the routine practice of post-transplantation CNS prophylaxis for ALL in the contemporary era, this position statement is anticipated to further stoke controversy and discussion within the transplantation community. Ultimately, only well-designed prospective clinical studies will elucidate the role of routine post-transplantation CNS prophylaxis.