Bone marrow microenvironment and disease development

doi:10.3969/j.issn.2095-4344.2013.01.020

Abstract

Abstract:

BACKGROUND: Bone marrow microenvironment change is closely related to the occurrence and development of hematopoietic disease.
OBJECTIVE: To review the cell and non-cell components in the bone marrow microenvironment as well as the regulatory role of signaling pathway and to investigate the relationship between bone marrow microenvironment change and disease development.
METHODS: A computer-based online retrieval of Pubmed database and Wanfang database was performed using the English key words “bone marrow niche, hematopoietic stem cell” and Chinese key words “bone marrow microenvironment, hematopoietic stem cells” to search papers published between January 2001 and April 2012. A total of 424 papers were retrieved and 61 were suitable for final analysis.
RESULTS AND CONCLUSION: The adult hematopoietic stem cells in bone marrow are the origins of blood and lymphocyte systems. Bone marrow microenvironment can support the self-renewal and differentiation of hematopoietic stem cells and it is composed of various kinds of hematopoietic cells, non-hematopoietic cells, extracellular matrix and other signal proteins. Normal bone marrow microenvironment plays an important role in sustaining the normal function of hematopoietic cells. Once the balance is broken, some malignant diseases such as leukemia and cancer would be caused. Therefore, further investigation of bone marrow microenvironment and understanding the regulatory mechanism and the determinative factor of stem cell fate will greatly facilitate bone marrow transplantation, tissue repair and regenerative medicine development.

Key words: stem cells, stem cell review, bone marrow, microenvironment, hemopoietic stem cells, bone marrow transplantation, blood diseases, mesenchymal stem cells, signal pathway, stem cell factors, 973 program

CLC Number:

R318

Shao Xiao-hu, Le Huang-ying. Bone marrow microenvironment and disease development[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(1): 124-130.

Figures/Tables 1

2.1 骨髓微环境的组成成分及功能骨髓微环境主要指造血干细胞的微环境，它能促使造血干细胞静息、更新、分化和迁移等。现在较为普遍的观点是存在两种造血干细胞 niche，一个附着在成骨细胞表面，另一个临近骨髓周血管表面，分别称为成骨细胞niche和内皮niche[1-4]。骨髓中填充的各种细胞、胞外矩阵成分、细胞因子等共同组成了复杂的微环境。 2.1.1 细胞成分骨髓微环境中居于核心地位的是造血干细胞，是成体干细胞最重要的组成部分，在整个生命过程中控制着造血系统生成淋系、髓系细胞，对各种血细胞的更新起着决定性作用。根据其造血重建能力可以分为长期造血干细胞(long-term hematopoietic stem cell, LT-HSC)、短期造血干细胞(short-term hematopoietic cell, ST-HSC)；造血干细胞继续向下分化形成多能造血祖细胞(multiple potential progenitor, MPP)，多能造血祖细胞再分化形成髓系祖细胞(common myeloid progenitor, CMP)和淋系祖细胞(common lymphoid progenitor, CLP)，进而分化和成熟成各种血细胞[5]。造血干细胞的含量非常少，主要分布在脊椎动物的长骨两端以及血管周围，但是其精确的生理定位仍然不是很清楚。成骨细胞系是首先发现的造血干细胞niche的组成成分，通过细胞间接触和信号分子调节造血干细胞的休眠和静息[6-7]。在骨髓腔内表面的成骨细胞niche，为长期造血干细胞提供休眠和静息的微环境，保持长期造血干细胞处于造血静息期和慢循环状态，维持干细胞数量稳定[8-9]。移植的造血干细胞出现在成骨细胞附近，通过非激活1A型BMP受体或者组成型激活PRP增加成骨细胞数量，继而增加造血干细胞数量[1-2]。成骨细胞分泌的成骨素和黏附分子ALCAM对造血干细胞有重要的调控功能[10]。Osterix+成骨祖细胞里的核糖核酸酶Dicer能显著影响造血平衡，但是成熟的osteocalcin+成骨细胞没有这种作用[11]。骨髓中存在着一类具有多向分化潜能的间充质干细胞。最近研究表明表达Nestin的间充质干细胞对造血干细胞niche具有重要的调控作用，Nestin+间充质干细胞和造血干细胞niche空间位置靠近，并且分布在周血管附近，更加靠近骨髓的中央区域，也在骨内膜出现[12]。它与交感神经系统的肾上腺素神经纤维相互接触，调节造血干细胞的移动，以及与造血干细胞数目波动的昼夜节律相关[12-13]。Nestin+间充质干细胞能表达高水平的造血干细胞维持因子，包括CXCL12，干细胞因子，血管细胞黏附分子1，成骨素等[12]。由于间充质干细胞具有免疫调节功能，在造血干细胞移植过程中，加入间充质干细胞能够提高移植成功率，一定程度上减轻移植物抗宿主病，并且有利于移植后组织修复[14]。研究发现巨噬细胞成为骨髓微环境的新成员。Chow等[15]分离Gr-1hi 和 Gr-1lo单核细胞和Gr1-F4/80+CD169+巨噬细胞，移除这些细胞会导致造血干细胞离开骨髓，且CD169+巨噬细胞扮演着关键角色。先前鉴定的osteomacs是F4/80+巨噬细胞，定位在骨内膜附近，移除后减少CXCL12和干细胞因子等转录，使得造血干细胞移动[16]。高表达CXCL12的网状细胞与造血干细胞和成骨细胞相邻，表达造血干细胞维持因子如CXCL12和干细胞因子，维持造血干细胞活性和静息[17-18]。脂肪细胞对造血微环境具有负向的调控功能，脂肪细胞含量多的部位造血干细胞和短期造血干细胞数量下降，脂肪含量少的小鼠移植的骨髓能够加速生成，恢复造血功能[19]。最近研究发现破骨细胞促进骨髓的造血干细胞niche形成和影响造血干细胞的归巢[20]。骨髓微环境中还存在着交感神经纤维，与其他细胞作用影响造血干细胞的移动[13, 21]。神经相关的非髓鞘许旺细胞，通过激活转化生长因子β维持造血干细胞休眠状态[22]，提示将会有更多神经细胞参与调控造血干细胞niche。 2.1.2 细胞外成分基质来源因子1(SDF1，CXCL12)和受体CXCR4是研究最透彻的调控因子。成骨细胞分泌SDF1，遭受辐射时该因子的表达上调[7]；同时血管细胞也分泌SDF1，两者都调控造血干细胞定位[18]。条件性敲除CXCR4 严重减少造血干细胞的数量，但是对成熟祖细胞的扩展没有影响[18]。CXCL12和CXCR4还对交感神经系统的昼夜节律调控产生应答，通过β3肾上腺素受体和粒细胞集落刺激因子起作用[13]。干细胞因子是一种转膜蛋白，与c-Kit组成信号对，最新的系统研究显示内皮细胞和表达瘦素受体的周血管基质细胞中的干细胞因子对于维持造血干细胞非常重要[23]。血管生成素1表达在成骨细胞上，与表达在造血干细胞和内皮细胞上的酪氨酸激酶受体2作用，维持造血干细胞niche中细胞静息状态[9]。近期研究表明，血管生成素样因子3在稳态和移植中都控制造血干细胞的静息和数量[24]。血小板生成素和受体MPL同时被删除，使得小鼠造血干细胞减少[25]，两者结合维持造血干细胞群体的静息状态[26]。突变血管生成素1和血小板生成素的其中任何一个都会增加造血干细胞的循环，导致造血干细胞的丢失以至耗尽[9, 26]。骨形态蛋白通过受体调节成骨细胞的数量进而控制niche大小和造血干细胞数量[2]；成骨细胞和内皮细胞表达的膜联蛋白，调节造血干细胞移植后的附着、归巢和移植[27]。骨桥蛋白是由成骨细胞和单核细胞产生的，结合整合素α4和CD44，是一个负调节子[28]。Cdc42是一种GTP酶，其条件性敲除小鼠使得造血干细胞的细胞循环进入激活状态，显著的增加了造血干细胞在骨髓中的数量和频率[29]。前列腺素E2能够影响骨髓微环境，优先延展短期造血干细胞，增加了其数量，但对长期造血干细胞没有负面影响，利于骨髓移植后造血的恢复[30]。 β1整合素具有征募细胞并且使它们留在骨髓中的功能，并且与Wnt信号途径交叉，调节造血干细胞的功能[31]。N-钙黏素表达在成骨细胞和静息期的造血干细胞中，可增加造血干细胞数量，但对其作用还存在着争议[32]。胞外矩阵中的组分对骨髓微环境具有重要作用[33]。SPP1是成骨细胞来源的胞外矩阵蛋白，影响造血干细胞数量和功能，其缺乏可导致长期造血干细胞增加，同时增加基质中的Jagged1和AngR1表达[34]。胞外矩阵中存在着多糖，多元醇类等组分对于形成趋化因子和生长因子的梯度可能具有一定的作用。胞外的无机成分中氧气和钙离子起到浓度梯度的诱导作用。氧气是胞外成份的重要组成部分。研究认为低氧分压维持胚胎干细胞、造血干细胞、间充质干细胞和神经干细胞的未分化状态，影响繁殖扩增和细胞命运[35]。缺氧能够激活多个干细胞体系中分子通路，调控Oct4和Notch信号[36]。表面受体Ca2+感受受体对于造血干细胞在归巢和niche中保留起重要作用[37]。 2.1.3 信号通路及分子调控在骨髓微环境中为了调控造血干细胞和间充质干细胞的更新和分化等过程，需要多条信号通路。经典的信号通路包括Notch、Wnt和Hedgehog等[38]。研究表明移植的造血干细胞在转基因动物中具有Notch活性，但是体内敲除研究不能肯定这个结果[39]。在甲状旁腺激素和受体模型中敲除Jagged1不影响造血干细胞的维持，对其分化也没有影响[40]，但是其功能还存在争议。甲状旁腺激素能够促进成骨细胞产生更多Jagged1，增加成骨细胞数量和造血干细胞的niche数目[1]。Hedgehog信号和Notch 信号作用途径相似[41]，通过激活骨形态发生蛋白途径延展造血干细胞[42]。还发现该信号途径对成人的造血平衡是必须的[41-42]。 Wnt信号通过Notch依赖的途径维持细胞未分化状态，但功能存在争议[43-44]。成骨细胞特异表达Wnt抑制子DKK1(dickkopf homolog 1)损害造血干细胞的自我更新[45]。同样，敲除SFRP1(secreted frizzled-related protein 1)导致长期造血干细胞起始增加，然后因过早成熟而耗尽[46]。表达成骨细胞的Wnt抑制因子1具有和过表达DKK1相似的表型[47]。前列腺素 E2 可稳定造血干细胞中的Wnt信号，通过该途径将造血干细胞和niche联系起来[48]。 2.2 骨髓微环境与疾病正常的骨髓微环境，对骨髓内细胞特别是造血干细胞和间充质干细胞，维持它们正常功能不可或缺的。在骨髓腔及周围有限的空间里，各种细胞、非细胞因子、细胞外基质以及内外的信号分子形成一个功能齐备的整体，共同控制着干细胞的自我更新、分化、移动等复杂精细的过程。维持骨髓微环境的稳态是保证人类及动物正常生命活动的必须条件。骨髓微环境对干细胞具有明显的调控作用。当人类或者动物年老之后，由于干细胞结合了细胞内部和环境来源的因子，使得这些干细胞移植的潜能和归巢能力下降[49]。环境改变了造血干细胞到达骨髓微环境的能力，也改变了造血干细胞niche的天然相互作用[50]。研究发现，当这些干细胞置于一个年轻的人类或动物的循环系统，或者在骨髓微环境中由存留的发挥长期调节作用的因子中和，如胰岛素样的生长因子1，可以恢复造血干细胞的功能[51]。因此，老年患者骨髓微环境的改变，可能来源于胞外成分的改变，使得造血干细胞及其他细胞功能发生改变，也与干细胞分化趋势发生改变可能相关，如随着年龄增长，脂肪细胞在骨髓内增多[19], 最近的综述中就论证了肥胖症与造血疾病的关系，另外指出毒素导致的DNA损害也是导致血液病的重要因素[52]。当骨髓微环境发生改变的时候，可能会变成恶性细胞生长的温床。白血病的发生除了遗传信息发生改变导致的积累效应之外，骨髓微环境的改变也会产生造血紊乱，甚至会引发相关疾病。有研究指出骨髓微环境的病变支持白血病干细胞生长[53]。白血病细胞生成骨髓niche，通过分泌大量的干细胞因子，扰乱原本的造血干细胞微环境，使得CD34+细胞数目下降，且在细胞因子的刺激下不能动员进入周血循环，从而抑制造血干细胞的正常造血功能[54]。骨髓移植之前，患者需要进行辐射治疗以杀死白血病细胞，但是同时会损害血管和骨髓微环境，影响恢复期的干细胞niche的重建，加大了移植失败的可能性[55]。另外，间充质干细胞由于产生了过量的转化生长因子β1，激活了T细胞和前炎症反应导致骨髓微环境异常，引发慢性特发性中性粒细胞减少症[56]。骨髓微环境的缺陷引起造血系统疾病，目前有两个机制解释。大量的证据支持恶性造血克隆诱导微环境功能的改变，结果创造了恶性细胞的生长条件，使用鼠模型研究显示初级微环境的缺陷也导致肿瘤[57]。可见，不论哪种致病机制，都与骨髓微环境改变有着很大关系。肿瘤浸润非恶性细胞，大多数都是骨髓来源的，包括巨噬细胞、骨髓来源的阻抑细胞、间充质干细胞和表达Tie2的单核细胞。遭到浸润的骨髓来源的阻抑细胞和间充质干细胞通过负向调节免疫反应产生前肿瘤化效应[58]。最近有研究显示人类间充质干细胞可能是癌相关成纤维细胞的来源之一[59]。还有一些研究显示骨髓微环境中间充质干细胞分泌的一些胞外分子能导致关节炎[60]。总之，骨髓微环境的异常会导致疾病发生，对人类及动物的健康甚至生命造成威胁。"

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