靶向白血病干细胞作为治疗的新策略

白血病干细胞被认为是白血病发生、发展及治疗后复发的根源,具有其特异的性状特征,以及自我更新、增殖和分化等能力.近年来以白血病干细胞作为治疗靶点已成为白血病治疗的一种新策略,目前的研究主要针对白血病干细胞表面分子、细胞内信号通路及与微环境的相互作用这三方面展开.对白血病干细胞的进一步认识将有助于提供新的更为有效的治疗靶点.     

Wnt信号通路调控造血干细胞自我更新的研究进展

造血干细胞是一类具有自我更新能力和分化成所有种类血细胞能力的多潜能干细胞,该类群细胞来源于中胚层细胞,最终定植于骨髓中。造血干细胞的增殖分化由多个信号通路精细调控,其中,Wnt信号通路在调控其自我更新的过程中具有重要作用。该文综述了多年来关于Wnt信号通路在脊椎动物(小鼠)造血干细胞自我更新中的研究,有助于了解Wnt信号通路的作用机制,也有望为改善体外增殖造血干细胞的效果提供理论支持。     

骨髓间充质干细胞向肝细胞分化的相关细胞因子及信号通路的研究进展

骨髓干细胞包括造血干细胞（HSCs）和间充质干细胞（MSCs）,骨髓间充质干细胞（BMSCs）是一类具有自我更新、增殖和多向分化能力的细胞,具有不对称分裂和无限增殖的特点。在肝细胞生长因子（HGF）的作用下,BMSCs可以分化为肝细胞,参与诱导这一分化过程的相关信号通路包括NF-kB信号通路、Notch信号通路、MAPK信号通路、Wnt信号通路和STAT3信号通路。文章主要就BMSCs分化为肝细胞的相关信号通路进行了综述。     

LFNG在白血病BALL-1细胞中的表达状况研究

O-岩藻糖肽3-β-N-乙酰氨基葡萄糖转移酶(Lunatic Fringe,LFNG)与Notch信号作用密切相关,且LFNG在不同组织细胞中对Notch信号所起的作用不同。为了探讨LFNG在急性B细胞白血病中的表达及对Notch信号的作用,应用real-time PCR和Western-blot在核酸水平及蛋白质水平上检测了LFNG在人急性B淋巴细胞白血病细胞系BALL-1、人正常B淋巴母细胞系HMy2.CIR及正常B细胞中的表达状况,并应用si RNA技术分析了LFNG基因沉默后对白血病BALL-1细胞中Notch信号通路的影响。结果显示:白血病细胞系BALL-1存在LFNG蛋白过度表达,且LFNG基因沉默后抑制白血病B细胞的Notch信号通路。上述结果提示LFNG在白血病B细胞中的异常表达能促进Notch信号。     

肿瘤细胞Hedgehog信号通路及其抑制剂

越来越多的证据显示, 肿瘤的发生、生长、转移、复发以及耐药等均与肿瘤干细胞密切相关.Hedgehog (Hh)信号通路调节胚胎发育和成体许多组织器官干细胞的自我更新与增殖.然而, 那些在正常发育过程中受到Hh信号通路调节的组织器官, 在该信号通路异常时常常发生肿瘤.这些肿瘤包括肝癌、神经胶质瘤、基底细胞癌、横纹肌肉瘤、胰腺癌、小细胞肺癌、胃癌、结肠癌、前列腺癌、黑色素瘤和多发性骨髓瘤等.介绍了近年来Hh信号通路在肿瘤发生和发展过程中的机制、在维持肿瘤干细胞自我更新方面的作用, 以及该通路的特异性抑制剂, 以显示其在肿瘤治疗中潜在的重要意义.最后, 提出了今后肿瘤干细胞Hh通路研究的重点和新思路.     

Notch信号通路对神经干细胞增殖分化的作用

神经干细胞作为一种具有自我更新能力和多向分化潜能的细胞,它的增殖和分化受到多种源于自身或外在、邻近或远程细胞信号通路的调控,各种细胞因子及胞间通讯在神经干细胞的增殖和分化中发挥着重要的作用。近年来的多种研究表明,Notch信号通路正是这样一种可以通过相邻细胞的配体与受体相互作用,从而传递信号,进一步发挥其生物学功能的重要信号通路。该通路参与了神经干细胞维持自我形态及向多种具有不同功能的神经细胞分化的过程．对于研究神经干细胞的增殖和分化具有巨大的意义。该文将就当前Notch信号通路对神经干细胞增殖分化影响的相关研究进行简要综述。     

白血病干细胞的生物学特性

白血病干细胞是第一个被确认的肿瘤干细胞,在白血病的形成和病情的发展中具有重要作用。深入研究其生物学特性将为白血病的发病机制以及干细胞靶向治疗奠定理论基础。该文介绍白血病干细胞的免疫表型、自我更新机制、生存优势及多重耐药等。     

白血病干细胞的分子调控

白血病干细胞(leukemic stem cell,LSC)的发现使得研究者能够更深入地阐释白血病的发病、复发、耐药等机制,为白血病的治疗开拓了新的研究途径和治疗方向.LSC与正常造血干细胞(hematopoietic stem cell,HSC)有许多相似之处,如都具有自我更新能力和多向分化潜能,同时又具有自身独特的生物学性质.LSC具有某些特殊的细胞表面标志;有其自身的细胞周期特点.本文主要介绍LSC的分子调控机制,同时简单回顾LSC的起源和特征,靶向治疗等研究进展.     

缓解与未缓解髓系白血病干细胞表面抗原CD34~+CD123~+表达差异研究

目的:探索缓解与未缓解急性髓系白血病干细胞表面抗原表达差异,为判定化疗疗效及其预后提供依据。方法:按照急性白血病诊断标准,根据患者入院时骨髓白血病细胞数量多少分成临床缓解与未缓解两组,以流式细胞仪分别检测骨髓中白血病干细胞表面相关抗原表达情况,比较二者之间差异。其中经标准化疗方案治疗结束后,通过复查骨髓象判定疗效并比较化疗前后白血病干细胞表面相关抗原表达变化。结果:与缓解的急性髓系白血病患者骨髓白血病干细胞相关抗原表达值相比,未缓解的患者骨髓白血病干细胞表面相关抗原表达明显升高,差异具有统计学意义(P0.05,0.001);未缓解的患者经标准方案化疗后骨髓虽然已经获得完全缓解,但依然具有白血病干细胞表面抗原高表达,提示这部分患者依然有复发的可能性。结论:急性髓系白血病患者的白血病干细胞相关抗原表达值升高是急性白血病复发难治的根源之一。     

Wnt信号在胚胎干细胞自我更新和分化中的作用

胚胎干细胞分离自胚泡内细胞团,具有无限自我更新和多向分化潜能,有很大的医学应用前景。Wnt家族是一类分泌型的细胞信号传导蛋白,可以通过复杂的信号传递通路调控胚胎的早期发育,对细胞的分化、增殖及生长具有重要的调节作用。该文就Wnt信号通路调节胚胎干细胞的自我更新和分化作一综述。     

调控软骨形成的信号通路及相关因子在骨髓间充质干细胞骨向分化中的作用*

骨髓间充质干细胞是一类具有自我复制和多向分化潜能的成体干细胞,可以通过定向诱导分化为成骨细胞、软骨细胞、脂肪细胞等,是目前骨再生医学和细胞治疗研究最多的理想种子细胞。在骨缺损的修复过程中,骨髓间充质干细胞内成软骨相关基因表达升高进而分化为软骨细胞,后期随着成骨细胞和破骨细胞的形成及血管长入,软骨基质逐步降解并被骨基质所替换。软骨细胞参与了骨缺损前期的修复过程,调控软骨形成的信号通路及相关因子不仅调控骨髓间充质干细胞成软骨细胞分化,同时在成骨细胞分化过程中也发挥着重要的作用。对调控软骨形成的信号通路及相关因子在骨髓间充质干细胞骨向分化中的调控作用和研究现状进行了总结,以期为临床寻找更好的治疗骨缺损的方法提供理论依据和研究方向。     

Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival

FLT3/FLK2, a member of the receptor tyrosine kinase family, plays a critical role in maintenance of hematopoietic homeostasis, and the constitutively active form of the FLT3 mutation is one of the most common genetic abnormalities in acute myelogenous leukemia. In murine hematopoiesis, Flt3 is not expressed in self-renewing hematopoietic stem cells, but its expression is restricted to the multipotent and the lymphoid progenitor stages at which cells are incapable of self-renewal. We extensively analyzed the expression of Flt3 in human (h) hematopoiesis. Strikingly, in both the bone marrow and the cord blood, the human hematopoietic stem cell population capable of long-term reconstitution in xenogeneic hosts uniformly expressed Flt3. Furthermore, human Flt3 is expressed not only in early lymphoid progenitors, but also in progenitors continuously along the granulocyte/macrophage pathway, including the common myeloid progenitor and the granulocyte/macrophage progenitor. We further found that human Flt3 signaling prevents stem and progenitors from spontaneous apoptotic cell death at least through up-regulating Mcl-1, an indispensable survival factor for hematopoiesis. Thus, the distribution of Flt3 expression is considerably different in human and mouse hematopoiesis, and human FLT3 signaling might play an important role in cell survival, especially at stem and progenitor cells that are critical cellular targets for acute myelogenous leukemia transformation.     

Generation of murine stromal cell lines supporting hematopoietic stem cell proliferation by use of recombinant retrovirus vectors encoding simian virus 40 large T antigen.

The bone marrow is a complex microenvironment made up of multiple cell types which appears to play an important role in the maintenance of hematopoietic stem cell self-renewal and proliferation. We used murine long-term marrow cultures and a defective recombinant retrovirus vector containing the simian virus 40 large T antigen to immortalize marrow stromal cells which can support hematopoiesis in vitro for up to 5 weeks. Such cloned cell lines differentially supported stem cells which, when transplanted, allowed survival of lethally irradiated mice, formed hematopoietic spleen colonies in vivo, and stimulated lymphocyte proliferation in vitro. Molecular and functional analyses of these cell lines did not demonstrate the production of any growth factors known to support the proliferation of primitive hematopoietic stem cells. All cell lines examined produced macrophage colony-stimulating factor. The use of immortalizing retrovirus vectors may allow determination of unique cellular proteins important in hematopoietic stem cell proliferation by the systematic comparison of stromal cells derived from a variety of murine tissues.     

骨髓间充质干细胞来源外泌体及其相关信号通路在激素性股骨头坏死中作用的研究进展*

骨髓间充质干细胞是具有多向分化能力的一种干细胞,近年来有关研究发现骨髓间充质干细胞分泌的外泌体具有促进损伤肌腱修复、血管生成、抑制氧化应激反应、保护神经细胞、促进软骨再生、调节骨代谢等功能。而激素性股骨头坏死是由于大量使用激素导致的股骨头无菌性坏死,其具体作用机制尚未阐明,相关信号通路,如Wnt/β-catenin、RANKL-RANK、PTEN/AKT、PI3K/AKT等通路在其中起着关键的作用,而这些信号通路的激活又与外泌体密切相关,综述了骨髓间充质干细胞来源外泌体及其相关信号通路在激素性股骨头坏死中作用的有关研究进展,以期对激素性股骨头坏死的防治及相关药物研发有一定指导意义。     

Normal hematopoiesis and hematologic malignancies: Role of canonical Wnt signaling pathway and stromal microenvironment

Wnts are a family of evolutionary-conserved secreted signaling molecules critically involved in a variety of developmental processes and in cell fate determination. A growing body of evidence suggests that Wnt signaling plays a crucial role in the influence of bone marrow stromal microenvironment on the balance between hematopoietic stem cell self-renewal and differentiation. Emerging clinical and experimental evidence also indicates Wnt signaling involvement in the disruption of the latter balance in hematologic malignancies, where the stromal microenvironment favors the homing of cancer cells to the bone marrow, as well as leukemia stem cell development and chemoresistance. In the present review, we summarize and discuss the role of the canonical Wnt signaling pathway in normal hematopoiesis and hematologic malignancies, with regard to recent findings on the stromal microenvironment involvement in these process and diseases.     

Heparan sulfate regulates self-renewal and pluripotency of embryonic stem cells

Embryonic stem (ES) cell self-renewal and pluripotency are maintained by several signaling cascades and by expression of intrinsic factors, such as Oct3/4 and Nanog. The signaling cascades are activated by extrinsic factors, such as leukemia inhibitory factor, bone morphogenic protein, and Wnt. However, the mechanism that regulates extrinsic signaling in ES cells is unknown. Heparan sulfate (HS) chains are ubiquitously present as the cell surface proteoglycans and are known to play crucial roles in regulating several signaling pathways. Here we investigated whether HS chains on ES cells are involved in regulating signaling pathways that are important for the maintenance of ES cells. RNA interference-mediated knockdown of HS chain elongation inhibited mouse ES cell self-renewal and induced spontaneous differentiation of the cells into extraembryonic endoderm. Furthermore, autocrine/paracrine Wnt/beta-catenin signaling through HS chains was found to be required for the regulation of Nanog expression. We propose that HS chains are important for the extrinsic signaling required for mouse ES cell self-renewal and pluripotency.