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类器官

维基百科，自由的百科全书
由Lgr5+细胞株培养生成的肠道类器官

类器官（英语：Organoid）是体外培养生成的立体细胞团，是特定器官的迷你简化版本，模仿该器官的关键功能、结构和生物复杂性。[1]类器官的培养可以起源于胚胎干细胞或者成体干细胞等多能性干细胞、人工诱导性多能干细胞以及癌症干细胞，这些细胞的自我更新以及分化潜能赋予其在立体培养条件下中自组装的能力。类器官的发展提供科学家与工程师在实验室中研究疾病与药物开发的简化模型。[2]协助个人化医疗、基因和细胞疗法、组织工程和再生医学等领域的发展。[3]

历史

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体外培养器官的始于一个解离再聚集实验[4]，科学家亨利·范·彼特斯·威森发现透过机械方式打散的海绵细胞可以自发性地重新聚集并组装成完整个体[5]。在随后的几十年中，多个实验室成功于两栖动物[6]和鸡胚胎[7]身上取得的器官组织重现解离后自组装的实验，在体外生成各类型的器官[4]。1975年，科学家透过共培养角质形成细胞和3T3纤维母细胞，首次在体外观察到第一个组织样细胞群的形成[8]。这些透过机械外力打散器官后的细胞再聚集与自组装的现象促致马尔科姆·斯坦伯格提出了差异黏附假说（Differential adhesion hypothesis，DAH）[4]。随着干细胞生物学的出现，科学家开始认识到干细胞在体外形成器官的潜力，因为观察到当其形成畸胎瘤或拟胚体时，分化的细胞可以组织成类似于在体内发现的各种组织类型[4]。类器官的出现始于细胞培养从二维平面基质转为三维立体基质的阶段，随着细胞外基质的发展，3D培养基方法的方法成为可能[9]，以允许器官立体结构的发育。[4]20世纪80年代末，米娜·贝塞尔及其同事证明，富含层粘连蛋白的凝胶可用作乳腺上皮细胞培养分化的基底膜[10][11]。如今，各类器官的培养方法已被提出并逐渐成熟[12]。在20世纪90年代，除了ECM提供细胞生长物理性质上的支持被提出外，还报导了ECM内的成分透过与基于整合素的黏着蛋白通路相互作用而影响基因表现[13]。2006年，Yaakov Nahmias和David Odde展示了血管肝类器官的自组装在体外环境维持了50多天[14]。2008年，日本理化学研究所的Yoshiki Sasai和他的团队证明，干细胞可以被诱导成神经细胞球并且自组织成独特的层状构造[15]。2009年，荷兰皇家艺术与科学研究所和乌特勒支大学的Hans Clevers实验室表明，单个表达LGR5的肠干细胞可以在体外自组织成隐窝绒毛结构并且无须提供间质区位，这使它们成为第一个类器官[16]。2010年，Mathieu Unbekandt和Jamie A. Davies证明了利用鼠胚衍生的肾干细胞可产生肾类器官[17]。2014年，王峮及其同事设计了基于I型胶原和层粘连蛋白的凝胶和合成泡沫生物材料，用于培养和运输肠道类器官[18]，并将DNA功能化的金纳米颗粒封装到肠道类器官中，成为可供药物运送与基因治疗的肠道特洛伊木马（intestinal Trojan horse）[19]。后续的研究显示这些类器官在体外[20]和体内同样具有显着的生理功能[21][22]。

其他重大的早期进展包括2013年，奥地利科学院分子生物技术研究所的Madeline Lancaster制定了一项流程，可以从多能干细胞开始生成模仿人类大脑细胞组织发育的大脑类器官[23]。荷兰皇家艺术与科学研究所和乌特勒支大学医学中心的Meritxell Huch与Craig Dorrell证明，来自受损小鼠肝脏的单个Lgr5+细胞可以在基于Rspo1的培养基中复制并扩增数个月并最终形成肝类器官[24]。2014年，伊利诺伊大学厄巴纳-香槟分校的Artem Shkumatov等人证明，通过调控胚胎干细胞粘附的基质硬度，可以形成心血管类器官。生理上的硬度特性促进了EB的立体性质与心肌分化[25]。2015年，Takebe等人通过将多能干细胞衍生的组织特异性祖细胞或相关组织样本与内皮细胞和间质干细胞相结合，展示了一种从不同组织形成器官芽的通用方法。他们认为，通过自组织凝聚原理产生的不太成熟的组织或器官芽可能是移植后重建成熟器官功能的最有效方法，而不是由发育上更加成熟阶段的细胞凝聚物[26]。

特性

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Lancaster和Knoblich[4]将类器官定义为从干细胞或器官前驱细胞发育而来的器官特异性细胞类型的集合，透过细胞分选和空间限制的谱系定型以类似于体内的方式进行自组织，并表现出以下特征特性：

  • 具备数种器官特异性的细胞类型。
  • 能够概括器官的特定功能（例如收缩、神经活动、内分泌、过滤、排泄）。
  • 细胞能够聚集并且自组装成为类似器官的功能性构造。

培养过程

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类器官的生长通常需要在立体培养基中培养干细胞或祖细胞[4]。干细胞具有自我更新和分化成各种细胞类型的能力，并且能够用于了解发育和疾病进展的过程[27]。因此，源自干细胞的类器官能够在器官水平上研究生理学[28]。立体培养基可以使用细胞外基质水凝胶（例如Matrigel或Cultrex BME）制成，这是一种富含层粘连蛋白的细胞外基质，由Engelbreth-Holm-Swarm肿瘤细胞株分泌[29]，可以通过将干细胞嵌入基质中来制备类器官[4]。当多能性干细胞用于创建类器官时，细胞通常（但并非总是）形成拟胚体[4]。然后用模式因子对这些拟胚体进行处理，以驱动所需类器官特征的形成[4]。此外，也可以使用目标器官中提取的成体干细胞创建类器官，并在立体培养基中培养[30]。

生物化学的特性已被纳入类器官培养中，借由添加形态发生素、形态发生抑制剂或生长因子，可以诱导胚胎干细胞或成体干细胞发育成为类器官。血管化技术可用于赋予微环境在生理上接近其相对应部位的特性。可以借由微流体系统、血管内皮生长因子输送系统和内皮细胞涂层模块来达成可促进氧气或营养物质进入类器官内部的血管系统[9]。利用源自患者的诱导多能干细胞（iPSC）[31]和基于CRISPR/Cas9的基因编辑技术[32]，可以生成基因组编辑或突变的多能干细胞（PSCs），并改变信号传递特性，以控制器官模型内的内在性质。

类型

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使用类器官可以概括多种器官结构[4]。本节旨在透过提供一份精简的器官模型清单，概述目前该领域的现状，并根据最新文献对每个器官模型进行简要概述，并提供其在研究中的应用示例。

脑类器官

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脑类器官是指体外培养的类似于大脑的微型器官。大脑类器官于旋转生物反应器在三维环境下中培养人类多能干细胞产生，并需要数月的时间发育[23]。这对脑部发育、生理学和功能的研究中具有潜在的应用。脑类器官可能会对外部刺激产生“简单的感觉”，神经科学家也对这些器官可能发展出感知能力表示担忧。他们提出，该技术的进一步发展需要受到严格的监督[33][34][35]。2023年，研究人员建造了一台混合生物计算机，将实验室培养的人脑类器官与传统电路相结合，可以完成语音识别等任务[36]。脑类器官目前正用于研究和开发类器官智能（OI）技术[37]。

胃肠道类器官

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胃肠道类器官是指概括胃肠道结构的类器官。胃肠道起源于内胚层，在发育过程中形成一个管状构造，可以分为三个不同的区域，与其他器官一起产生胃肠道的以下部分：[4]

  1. 前肠发育形成口腔和胃
  2. 中肠发育形成小肠和升结肠
  3. 后肠发育形成结肠的其余部分和直肠

胃肠道类器官又可细分为以下数种：

肠类器官

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迄今为止，肠类器官[16]属于直接由肠组织或多能干细胞产生的肠道类器官[4]。促使人类多能干细胞形成肠类器官的方法是，首先使用激活素A驱动细胞进入中内胚层状态，然后对Wnt3a和Fgf4信号通路进行上调，因为它们已被证明可以促进组织走向后肠道细胞命运[4]。肠类器官也可以由肠干细胞产生，从成体组织中提取并在立体培养基中培养[30]。这些成体干细胞衍生的类器官通常被称为肠类器官或类结肠类器官，具体取决于它们的起源部分，并且是从人类和小鼠肠道中建立的[16][38][39]。肠类器官由围绕中央管腔的单层极化肠上皮细胞组成。因此，通过概括肠道的功能、生理学和组织，并维持结构中正常存在的所有细胞类型（包括肠干细胞），概括肠道的隐窝绒毛结构[4]。因此，肠类器官是研究肠道营养转运[40][41]、药物吸收和递送[42][43]、纳米材料和纳米医学[44][45]、肠泌素分泌[46][47]和各种肠道病原体感染[48][49]等议题的有力模型。

例如，王峮团队利用肠类器官衍生的粘膜模型设计了人工病毒纳米颗粒作为口服药物递送载体（ODDV）[50]，并展示了利用新建立的结肠类器官作为高通量药物筛选、毒性分析工具的新概念。测试和口服药物开发[51]。肠类器官还以如此高的保真度再现了隐窝绒毛结构，以至于它们已成功移植到小鼠肠道中，因此被高度视为有价值的研究模型[4]。肠类器官已被利用的研究领域之一是干细胞生态位。肠类器官被用来研究肠干细胞区位的性质，并证明了IL-22在维持肠干细胞中的重要作用[52]以及其他细胞类型（如神经元和成纤维细胞）在维持肠道干细胞的重要性[30]。在感染生物学领域，人们已经探索各类基于肠道类器官的模型系统。一方面，只需将类器官与感兴趣的肠道病原体混合即可大量感染[53]。然而，为了模拟更接近自然情况下，由肠腔开始的感染途径，需要使用病原体进行显微注射[54][55]。此外，肠类器官的极性可以反转[56]，甚至可以解离成单个细胞并以二维单层培养[57][58]，以便使上皮的顶端和基底外侧更容易接近。最后，肠类器官也显示出用于治疗的潜力[59]。

显微镜下肠类器官Mini-Gut生长的代表图。比例尺为200微米。

为了更准确地再现体内肠道，开发了肠道类器官和免疫细胞的共培养方式[58]。此外，器官芯片模型将肠道类器官与其他细胞或体内环境（例如内皮细胞、免疫细胞以及蠕动）结合起来[60][61]。

胃类器官

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胃类器官部分地概括了胃的生理性质。通过在三维培养条件下对FGF、WNT、BMP、视黄酸和EGF信号通路进行时间尺度上的调控，可以从多能干细胞直接生成胃类器官[62]。胃类器官也可以由LGR5+的胃成体干细胞产生[63]。胃类器官已被用作研究癌症[64][65]以及其他人类疾病发育的模型[62]。例如，一项研究[65]调查了患者转移性肿瘤背后的潜在遗传变化，发现相较于同一患者身上的原发性肿瘤，转移性肿瘤的TGFBR2基因的两个等位基因均发生突变。为了进一步评估TGFBR2在转移中的作用，研究人员创建了TGFBR2基因敲落的类器官，透过这种类器官，他们证明TGFBR2活性降低会导致体内与体外环境下的恶性肿瘤侵袭与转移。

舌类器官

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舌类器官是概括舌头生理学各方面的类器官。在立体培养条件下，透过EGF、WNT和TGF-β的调控，使用表达BMI1的上皮干细胞培养出上皮舌类器官[66]。然而，这种类器官培养物缺乏味觉受体[66]。相较之下，含有味觉细胞的味蕾类器官则是使用LGR5+或CD44+的轮状乳突干细胞/前驱细胞[67]或者Lgr5+或LGR6+的味觉干细胞创建的[68]。

其他

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胸腺是负责T细胞成熟的淋巴器官。胸腺类器官部分概括了胸腺的结构以及干细胞区位的功能[71]。胸腺类器官的培养是借由在立体培养环境中接种胸腺基质细胞而达成的[71]。由于其成功再现胸腺的功能，因此可以借由共培养人类造血干细胞/骨髓干细胞与小鼠胸腺类器官产生T细胞[71]。
  • 睾丸类器官[72]
  • 前列腺类器官[73]
  • 肝脏类器官[74]。近期的研究表明，该技术在协助戊型肝炎的新药开发上十分有效，因为它可以重现整个病毒生命周期[75]。
细胞排斥性微量滴定板的最新进展使得能够快速、经济高效地筛选大分子药物（例如针对胰腺癌3D模型的库）。这些模型在表型和表达谱上与David Tuveson博士实验室发现的模型一致。

现今，来自患者的外植体（patient derived explants，PDX）或直接来自癌症组织的三维器官模型已经可以轻易制备，并且可将其用于现有核准药物的高通量筛选。

由脑微血管内皮细胞（BMECs）、星形细胞和周细胞组成的自组装细胞聚集体正逐渐成为物质穿膜和微流体模型的潜在替代方案。这些器官模型能够生成血脑屏障（BBB）的许多特征，如紧密连接的表达、分子运输蛋白和药物排出泵，因此可以用来模拟药物穿越BBB的过程。此外，它们可以作为评估BBB与相邻脑组织之间相互作用的模型，并提供了一个了解新药物克服BBB的综合能力以及其对脑组织的影响的平台。此类模型具有高度可扩展性，且比微流体装置更容易制造和操作。然而，它们对于重建BBB的形态和生理学以及模拟生理流动和剪应力的能力有限[103]。

基础研究

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类器官能够协助研究细胞与细胞间、细胞与环境之间的相互作用以及疾病和药物如何影响他们的作用。体外培养使该系统易于操作及监测。器官的实际体积过大使得物质渗透受到限制而不易培养，但类器官的小尺寸可以规避此问题。另一方面，类器官并不表现出所有器官特征，并且与其他器官的相互作用在体外也无法重现。虽然肠道类器官的第一个研究方向是用于探讨干细胞特性的调控[16]，但如今也用于研究营养物质的摄取、药物转运和肠泌素的分泌等议题[104]。这对于吸收不良疾病以及肥胖、胰岛素抵抗和糖尿病等代谢疾病具有重要意义。

疾病模型

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类器官提供建立人类疾病细胞模型的机会，可以在实验室中进行研究以更好地了解疾病的原因并确定可能的治疗方法。类器官在这方面的潜力首次在小头畸形的遗传研究中显现，其中患者细胞被用来制造脑类器官，这种类器官较小并且在早期神经元生成中表现出异常[23]。另一个案例是将CRISPR应用于人类多能干细胞，在与两种不同肾脏疾病（多囊肾病和局灶节段性肾小球硬化症）相关的基因中引入靶向突变[83]。这些经过CRISPR修饰的多能干细胞随后被培养成人类肾类器官，表现出疾病特异性表型。来自患有多囊肾病突变的干细胞的肾脏类器官由肾小管形成了巨大的半透明囊肿结构。当在悬浮的情况下培养时，这些包囊的大小在数个月内达到直径1厘米[105]。与局灶节段性肾小球硬化症相关的基因发生突变的肾类器官，其足细胞（该疾病中受影响的过滤细胞）之间出现了细胞连接的缺陷[106]。重要的是，这些疾病表型在具有相同遗传背景但缺乏CRISPR突变的对照类器官中不存在[83][105][106]。将这些类器官表型与小鼠和人类的患病组织进行比较，发现它们与早期发育缺陷有相似之处[105][106]。

正如Takahashi和Yamanaka于2007年首次发表的那样，诱导多能干细胞（iPSC）也可以从患者皮肤纤维母细胞中重编程[107]。这些干细胞携带患者的确切遗传背景，包括可能导致人类疾病发展的任何基因突变。由于ORCL1突变而患有Lowe综合征的患者已将这些细胞分化为肾脏类器官[108]。该报告比较了患者iPSC与不相关的对照iPSC分化的肾类器官，并证明患者肾细胞无法调动高尔基体中的转录因子SIX2[108]。因为SIX2是肾单元前驱细胞的一个明确标记，作者得出结论为，洛氏综合征（近曲小管在吸收的整体衰竭或范康尼氏症候群）中常见的肾脏疾病可能与肾单元引起的改变有关，其中祖细胞缺乏这种重要的SIX2基因表达[108]。

其他研究使用CRISPR来修复患者iPSC细胞中的突变，以创建等位基因对照，该对照可以与iPSC重编程同时进行[109][110][111]。将患者iPSC衍生的类器官与同基因对照进行比较是该领域当前的黄金标准，因为它允许将感兴趣的突变分离为实验模型中的唯一变量[112]。在一份报告中，将源自IFT140复合杂合突变的Mainzer-Saldino综合征患者iPSC的肾类器官与等基因对照类器官进行比较，其中通过CRISPR修正了产生无活性mRNA转录物的IFT140突变体[110]。患者肾类器官表现出与现有动物模型一致的异常纤毛形态，在基因修正的类器官中将其恢复为野生型状态[110]。比较患者和对照类器官中纯化的上皮细胞的转录组突显了涉及细胞极性、细胞-细胞连接和动力蛋白运动组装的途径，其中一些途径与肾纤毛病表型家族中的其他基因型有关[110]。另一份利用等基因对照的报告表明，先天性肾病综合征患者产生的肾脏类器官的肾小球中去氧肾上腺素定位异常[111]。

最后，诸如上皮代谢之类的事情也可以利用类似方式建模[113]。

个人化医疗

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Clevers小组建立的方法可以从直肠活检样本中培养出的肠类器官，目前已被用于模拟囊肿性纤维化[114]，并促使类器官首次运用于个人化医疗[115]。囊肿性纤维化是一种遗传性疾病，由囊肿性纤维化穿膜传导调节基因（Cystic fibrosis transmembrane conductance regulator，CFTR）的突变引起，该基因编码位于健康上皮表面维持液体所需的离子通道。Jeffrey Beekman实验室于2013年进行的研究描述，以毛喉素或霍乱毒素等cAMP升高激动剂刺激结直肠类器官，会以完全CFTR依赖性的方式诱导类器官快速肿胀[114]。非囊肿性纤维化患者的类器官因为液体输送到类器官管腔而对毛喉素产生反应并膨胀，相较之下，来自囊肿性纤维化患者的类器官则严重减少或不存在。修复CFTR蛋白的疗法可以恢复肿胀，这表明可以在临床前实验室环境中量化个体对CFTR调节疗法的反应。2013年，Schwank等人于更进一步证明肠道囊肿性纤维化类器官的异常表型可以透过CRISPR-Cas9基因编辑进行修复[116]。

2016年，Dekkers等人的后续研究表明，来自囊肿性纤维化患者的肠道类器官之间由毛喉素诱导的肿胀程度差异与已知的诊断和预后标志物（例如CFTR基因突变或CFTR功能的体内生物标记）相关[115]。此外，他们证明具有特定CFTR突变的肠道类器官接受CFTR调节剂处里后的效果与已发表的临床试验结果相似。这促使临床前研究发现来自具有极其罕见的CFTR突变且未经过治疗的患者类器官对临床使用的CFTR调节剂有强烈反应。这些临床前类器官测试所得到的治疗成效被后续Kors van der Ent所带领的团队执行的临床试验所证实。这些研究首次表明类器官可以应用于个人化医疗。

类器官移植

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2022 年，类器官被首次用于移植手术。一名患有溃疡性结肠炎的患者，借由采集其健康结肠黏膜的细胞进行体外培养1个月后，将这些细胞生长而成的类器官重新移植回患者身上，取得良好的治疗效果[117][118]。

作为发育生物学的模型

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类器官为研究人员提供了研究发育生物学的模型[119]。自从多能干细胞被提出后以来，利用二维培养在体外定向诱导多能干细胞的分化已经取得了巨大的进展[119]。如今，多能性干细胞培养的技术进步搭配3D培养技术的发展，使得培养各类器官内的特定细胞组织成为可能[119]。因此，这些类器官的使用极大地促进了我们对器官发生过程和发育生物学领域的理解[119]。例如，中枢神经系统的发育中，类器官的研究有助于科学家理解视神经盘形成过程中物理力量的扮演的角色[119][120]。近期的研究则专注于延长皮质类器官的生长周期并且取得显著的进展。在一些研究中，类器官存在将近一年，并表现出人类胎儿发展阶段的部分特征[121]。

参见

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