CN117241806A - 用于预防或治疗肾病的组合物 - Google Patents
用于预防或治疗肾病的组合物 Download PDFInfo
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- CN117241806A CN117241806A CN202280018253.4A CN202280018253A CN117241806A CN 117241806 A CN117241806 A CN 117241806A CN 202280018253 A CN202280018253 A CN 202280018253A CN 117241806 A CN117241806 A CN 117241806A
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- kidney
- protein
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- stem cells
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Abstract
根据本公开内容的肾器官来源的干细胞或类器官:易于应用于治疗性程序;由于其高自我增殖率可大量供应;具有分化成肾细胞的高度潜力;极不可能形成肿瘤;并且具有优异的当直接注射到病灶中时使受损组织再生的能力。因此,干细胞尤其可非常适合用于基于成体干细胞的再生治疗。另外,根据本发明的组合物可以在肾细胞中特异性地仅选择肾干细胞。此外,表达Lrig1蛋白的肾干细胞或表达编码Lrig1蛋白的基因的肾干细胞就更新能力和多能性而言是极好的,并且具有分化为肾单位的潜力,并因此可以在预防或治疗肾病方面得到非常有效的应用。
Description
技术领域
本发明涉及用于预防或治疗肾病的组合物。
背景技术
肾是维持身体的稳态、调节体液的量以及血液中的离子浓度和pH、排泄废物产物(例如代谢废物产物、毒素和药物)、调节血压、并进行其他代谢内分泌功能的重要器官。另外,肾激活帮助钙在小肠中被吸收的维生素D,并且还参与多种激素的合成。肾病是指肾不能正常进行排泄、调节、代谢和内分泌功能,并且其整体功能降低或异常的病症。由于肾损伤而导致的肾功能下降导致肾及相关结构增大、肾的萎缩、体液量改变、电解质失衡、代谢性酸中毒、气体交换的障碍、抗感染功能受损、尿毒症毒素的积累等。特别地,急性肾衰竭是通过由于多种原因而导致的肾功能下降引起的具有高死亡率的难治性疾病。即使肾功能恢复,根据损伤的原因和严重程度,急性肾衰竭可能复发,或者如果未经治疗的话,则可进展为慢性和终末期肾衰竭。
虽然有现代医学的发展,但许多入院的患者经受肾功能下降,并且特别地,在许多情况下,疾病严重性高的患者由于肾功能下降而需要肾替代治疗。已报道了急性肾损伤的患病率从住院患者的约5%至入住重症监护室患者的约30%至50%,并且虽然开发了新的治疗方法,但这一患病率仍在稳步提高。
为了治疗这样的肾病,目前正在积极进行对干细胞的临床前报告和临床试验。具体地,已经以多种方式研究了多种类型的干细胞(包括间充质干细胞、脂肪来源的干细胞、羊水干细胞和肾祖细胞)以修复肾。在这些干细胞中,特别是使用来源于成体肾的成体干细胞的细胞治疗产品具有改善肾移植和分化的潜在益处,并且可以非常有效地用于自体治疗。
在该背景下,就肾而言,已报道了成体干细胞存在于近端小管末端、肾小球和肾乳头中,并且已经对能够通过这样的干细胞诱导受损肾细胞再生的细胞治疗产品进行了多种研究。
然而,对这样的肾干细胞的鉴定、鉴定干细胞作为治疗剂应用及其用于临床使用的适用性的研究仍然不足。
发明内容
技术问题
本发明的一个目的是提供用于预防或治疗肾病的药物组合物,其含有肾组织来源干细胞作为活性成分。
本发明的另一个目的是提供用于产生肾类器官的方法、由此产生的肾类器官、和用于预防或治疗肾病的含有肾类器官作为活性成分的药物组合物。
本发明的又一个目的是提供用于检测肾组织来源干细胞的组合物,以及包含所述组合物的用于检测肾组织来源干细胞的试剂盒。
本发明的又一个目的是提供用于检测肾组织来源干细胞的方法和用于分离肾干细胞的方法。
本发明的再一个目的是提供用于培养肾组织来源干细胞的方法。
然而,本发明要实现的目的不限于上述目的,并且本领域技术人员从以下说明书中将清楚地理解本文中未提及的另外的目的。
技术解决方案
1.含有肾组织来源干细胞作为活性成分的药物组合物
本发明的一个实施方案提供了用于预防或治疗肾病的药物组合物,其含有肾组织来源干细胞作为活性成分。
本发明的肾组织来源干细胞表达Lrig1(富含亮氨酸重复和免疫球蛋白样结构域1)蛋白或表达编码Lrig1蛋白之基因。
根据本发明,表达Lrig1的肾上皮细胞或表达编码Lrig1之基因的肾上皮细胞是具有干性的肾组织来源干细胞,与其他细胞不同,并且特别地,这些细胞参与管生成(Tubulogenesis)(肾发育晚期),并且能够分化为肾单位。因此,出于本发明的目的,当使用具有干性的表达Lrig1的肾上皮细胞或表达编码Lrig1之基因的肾上皮细胞时,可以非常有效地预防或治疗肾病。
本发明中的“Lrig1”是与受体酪氨酸激酶(例如EGFR家族、MET和RET蛋白)相互作用的跨膜蛋白。Lrig1可来源于哺乳动物(包括灵长类(例如人和猴)、啮齿动物(例如小鼠和大鼠)等),并且可以是例如人Lrig1(由登记号:NM_015541或NP_056356编码的多肽,或由SEQ ID NO:1表示的多肽),而不限于此。
在本发明中,肾组织来源干细胞还可表达Klf6(Krueppel样因子6)蛋白或表达编码所述Klf6蛋白之基因。
本发明中的“Klf6”是由对应于肿瘤抑制基因的KLF6基因编码的蛋白质。Klf6可来源于哺乳动物(包括灵长类(例如人和猴)、啮齿动物(例如小鼠和大鼠)等),并且可以是例如人Lrig1(由登记号:NP_001153596.1或NM_001160124.1编码的多肽;由NP_001153597.1或NM_001160125.1[Q99612-3]编码的多肽;由NP_001291.3或NM_001300.5[Q99612-1]编码的多肽,或由SEQ ID NO:2表示的多肽),而不限于此。
本发明中的“肾组织来源干细胞”是存在于肾组织中的干细胞,并且是指能够分化为肾的所有细胞类型的自我更新和多能性干细胞。这些干细胞可参与受损肾的再生和肾的稳态。
本发明的肾组织来源干细胞可用作细胞治疗产品。
本发明中的“细胞治疗产品”是在治疗方法中使用的活细胞(在治疗方法中它们被直接注射到患者中),并且是指通过物理、化学或生物方法(包括这些细胞的体外培养、增殖或选择)操作活的自体细胞、同种异体细胞或异种细胞而制备的药物产品。出于本发明的目的,肾组织来源干细胞表达存在于患者肾中的Lrig1蛋白或表达编码Lrig1蛋白之基因、具有优异的干性,并因此具有副作用很少(例如移植排斥)的优点。
本发明中的“肾病”是引起肾功能减弱的疾病,并且根据肾功能恶化的速度,其一些实例包括急性肾损伤(acute kidney injury,AKI)或慢性肾病(chronic kidneydisease,CKD)。例如,所述肾病可以是急性肾损伤,而不限于此。
本发明中的肾病可以是例如选自以下中的至少一种:肾小球肾炎、慢性肾衰竭、急性肾衰竭、肾病综合征、肾盂炎、肾结石和肾癌,而不限于此。
本发明中的“预防”意指降低动物中病理细胞的发生程度或对细胞的损伤或细胞的损失。预防可以是完全的或部分的。在这种情况下,预防可意指这样的的现象:其中与不使用用于预防和治疗肾病的组合物的情况相比,在对象中病理细胞或异常免疫功能的发生减少。
本发明中的“治疗”是指与出于改变接受治疗的对象或细胞的自然过程之目的的临床干预相关的任何行为,并且可以用于预防而进行或在临床病理状态的过程期间进行。治疗的期望效果可包括预防疾病的发生或复发、或者减轻症状、或者减少疾病的任何直接或间接的病理后果、或者预防转移、降低疾病进展的速度、改善或减轻疾病状态、或者改善预后。即,术语“治疗”可被解释为涵盖通过组合物减轻或治愈肾病症状的任何行为。
本发明的肾组织来源干细胞可以以选自以下中的任一种剂量来施用:1×107至1×108、1×108至2×108、2×108至4×108、4至108至6×108、6×108至8×108、8×108至1×109、1×109至2×109、2×109至4×109、4×109至1×1010、2×108至6×108、6×108至1×109、1×108至2×108、2×108至2×109、1×107至1×108、1×108至1×109、1×109至1×1010、以及1×107至1×109个细胞/kg,而不限于此。
在本发明中,药物组合物可以是胶囊剂、片剂、颗粒剂、注射剂、软膏剂、散剂或饮料的形式,并且所述药物组合物可以用于施用于人。
对于使用,本发明的药物组合物可以根据各自的常规方法以经口制剂(例如散剂、颗粒剂、胶囊剂、片剂和水混悬剂)、外用制剂、栓剂和无菌可注射溶液剂的形式配制,而不限于此。本发明的药物组合物还可含有可药用载体。作为可药用载体,黏合剂、润滑剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、助悬剂、着色剂、矫味剂等可用于经口施用;缓冲剂、防腐剂、疼痛缓解剂、增溶剂、等张剂、稳定剂等可用于注射;并且基质、赋形剂、润滑剂、防腐剂等可用于表面施用。另外,本发明的药物组合物可以通过与如上所述的可药用载体混合来以多种剂型制备。例如,对于经口施用,可将药物组合物以片剂、锭剂、胶囊剂、酏剂、混悬剂、糖浆剂、糯米纸囊剂等的形式配制。对于注射,可将药物组合物以单位剂量安瓿或以多剂型的形式配制。另外,药物组合物可配制成溶液剂、混悬剂、片剂、胶囊剂、持续释放制剂等。
同时,适合于配制的载体、赋形剂和稀释剂的一些实例包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。另外,药物组合物还可含有填充剂、抗凝剂、润滑剂、湿润剂、矫味剂、乳化剂、防腐剂等。
根据本发明药物组合物的施用途径包括但不限于经口、静脉内、肌内、动脉内、髓内、硬膜内、心内、经皮、皮下、腹膜内、鼻内、经肠胃、表面、舌下和直肠内途径。例如,施用的途径可以是经口或肠胃外施用。
在本发明中,“肠胃外”包括皮下、皮内、静脉内、肌内、关节内、滑膜内、胸骨内、硬膜内、病灶内和颅内注射或输注技术。出于本发明的目的,药物组合物可以通过直接注射到肾中来施用,而不限于此。
本发明的药物组合物的施用剂量可根据多种因素而变化,包括所使用的具体化合物的活性、患者的年龄、体重、一般健康状况、性别、饮食、施用的时间、施用的途径、排泄率、药物组合以及待预防或治疗的特定疾病的严重程度。虽然药物组合物的剂量根据患者的状况和体重、疾病的严重程度、药物的形式、施用的途径和施用的持续时间而变化,但可由本领域技术人员适当选择。药物组合物可以以0.0001至50mg/kg/天或0.001至50mg/kg/天的剂量施用。药物组合物可一天施用一次或多次。剂量不以任何方式限制本发明的范围。根据本发明的药物组合物可以配制为丸剂、糖包衣片剂、胶囊剂、液体剂、凝胶剂、糖浆剂、浆剂或混悬剂。
2.类器官
本发明随后将要描述的肾类器官易于应用于治疗、由于其高自我更新能力而可以大量供应、具有优异的分化成肾细胞的能力、不太可能形成肿瘤、并且具有优异的当直接注射到病灶中时使受损组织再生的能力。因此,类器官可非常适合用于基于成体干细胞的再生治疗。特别地,与基于间充质干细胞、胚胎干细胞或去分化多能干细胞的现有细胞治疗产品相比,这些肾类器官有利地具有优异的直接再生作用。
在下文中,将详细描述肾类器官、用于产生肾类器官的方法及其用途。
(1)肾类器官
本发明的另一个实施方案提供了肾类器官。
本发明的肾类器官包含表达Lrig1蛋白的肾组织来源干细胞或包含表达编码Lrig1蛋白之基因的肾组织来源干细胞。
根据本发明的表达Lrig1的肾上皮细胞或表达编码Lrig1之基因的肾上皮细胞是具有干性的肾组织来源干细胞,与其他细胞不同,并且特别地,这些细胞参与管生成(肾发育晚期),并且能够分化成肾单位。因此,出于本发明的目的,具有干性的表达Lrig1的肾上皮细胞或表达编码Lrig1之基因的肾上皮细胞能够非常有效地形成类器官。
在本发明中,肾组织来源干细胞还可表达Klf6蛋白或编码所述Klf6蛋白之基因。
在本发明的肾类器官中,关于Lrig1或Klf6蛋白或编码其的基因、肾组织来源干细胞等的内容与以上在“1.含有肾组织来源干细胞作为活性成分的药物组合物”中描述的相同,并因此其描述将被省略。
本发明中的“类器官”是指具有3D结构的细胞,并且是指通过人工培养过程产生,而不是从动物等中收集或获得的组织样模型。与2D培养不同,3D细胞培养允许细胞在体外向所有方向生长。
(2)用于产生肾类器官的方法
本发明的另一个实施方案提供了用于产生肾类器官的方法。
根据本发明的用于产生肾类器官的方法包括以下的步骤:(a)从分离自目的对象的肾上皮细胞中分离表达Lrig1(富含亮氨酸重复和免疫球蛋白样结构域1)蛋白的细胞或分离表达编码Lrig1蛋白之基因的细胞;(b)培养表达Lrig1蛋白的细胞或培养表达编码Lrig1蛋白之基因的细胞;以及(c)由在基质胶中培养的细胞形成类器官。
根据本发明,表达Lrig1的肾上皮细胞或表达编码Lrig1之基因的肾上皮细胞是具有干性的肾组织来源干细胞,与其他细胞不同,并且特别地,这些细胞参与管生成(肾发育晚期),并能够分化成肾单位。因此,出于本发明的目的,当使用具有干性的表达Lrig1的肾组织来源干细胞或表达编码Lrig1之基因的肾组织来源干细胞时,可以以非常高的产率产生肾类器官。
另外,在本发明的步骤(a)中分离的细胞可表达Klf6(Krueppel样因子6)蛋白或编码Klf6蛋白之基因。
在根据本发明的用于产生肾类器官的方法中,关于Lrig1或Klf6蛋白或编码其的基因、肾组织来源干细胞、类器官等的内容与以上在“1.含有肾组织来源干细胞作为活性成分的药物组合物”和“(1)肾类器官”中描述的相同,并因此其的描述将被省略。
在本发明中,分离细胞的步骤(a)可在将分离自目的对象的样品解离之后,根据常规方法通过磁性活化细胞分选(Magnetic activated cell sorting,MACS)或流式细胞术分析来进行,而不限于此。
在本发明中,解离样品的步骤可使用胶原酶来进行,而不限于此。
在本发明中,培养表达基因的细胞的步骤(b)可使用含有胎牛血清、生长因子和抗生素的细胞培养基来进行。
在本发明中,形成类器官的步骤(c)可使用含有B27补充剂、条件培养基、生长因子、N-乙酰半胱氨酸和ALK 5(TGFβ激酶/激活素受体样激酶)抑制剂的细胞培养基来进行。
本发明中的“生长因子”是细胞生长所必需的物质,并且其的一些实例包括但不限于血管内皮生长因子(vascular endothelial growth factor,VEGF)、肝细胞生长因子(hepatocyte growth factor,HGF)、胰岛素样生长因子(insulin-like growth factor,IGF)、表皮生长因子(epidermal growth factor,EGF)、成纤维细胞生长因子(fibroblastgrowth factor,FGF)等。
本发明中的“条件培养基”可以是选自Wnt3a条件培养基、Noggin条件培养基和Rspol条件培养基中的至少一种。例如,培养基可含有Wnt3a条件培养基、Noggin条件培养基和Rspo1条件培养基,例如40% Wnt3a条件培养基、10% Noggin条件培养基和10% Rspo1条件培养基,而不限于此。
本发明中的“细胞培养基”可以含有用于细胞系体外生长和维持的基本组分,并且可以是例如Dulbeco改良Eagle培养基(Dulbeco’s Modified Eagle’s Medium,DMEM)、最小必需培养基(Minimal Essential Medium,MEM)、基础培养基Eagle(Basal Medium Eagle,BME)、RPMI-1640、DMEM/F10、DMEM/F12、ADMEM/F12、Glasgow最小必需培养基(Glasgow’sMinimal essential Medium,GMEM)、Iscove改良Dulbecco培养基(Iscove’s ModifiedDulbecco’s Medium,IMDM)等。步骤(b)中的细胞培养基可以是RPMI-1640,并且步骤(c)中的细胞培养基可以是ADMEM/F12,而不限于此。
在本发明的一个实施方案中,在步骤(b)中,细胞培养基可含有10%胎牛血清、20ng/ml表皮生长因子(EGF)和1%青霉素-链霉素,而不限于此。
在本发明的一个实施方案中,在步骤(c)中的细胞培养基可含有1.5%B27补充剂、40% Wnt3a条件培养基、10% Noggin条件培养基、10% Rspo1条件培养基、50ng/ml EGF、100ng/ml FGF-10、1.25mM N-乙酰半胱氨酸和5μM A8301(CAS号:909910-43-6),而不限于此。
本发明中的基质胶可以是生长因子减少的基质胶,而不限于此。
(3)肾类器官
本发明的又一个实施方案提供了通过根据本发明用于产生肾类器官的方法产生的肾类器官。
本发明的肾类器官是使用表达Lrig1的肾组织来源干细胞或使用表达编码Lrig1之基因(优选Lrig1和Klf6蛋白或编码其的基因)的肾组织来源干细胞(其具有优异的干性)产生的。这些肾类器官通过非常有效地模拟肾,使得有效地筛选肾损伤治疗剂成为可能,并且还可直接用作肾损伤的细胞治疗剂。
在本发明的肾类器官中,关于Lrig1或Klf6蛋白或编码其的基因、肾类器官及用于产生其的方法等的内容与以上在“1.含有肾组织来源干细胞作为活性成分的药物组合物”和“(1)肾类器官”中描述的相同,并因此其的描述将被省略。
(4)用于预防或治疗肾病的药物组合物
本发明的另一个实施方案提供了用于预防或治疗肾病的药物组合物,其含有肾类器官作为活性成分。
本发明的肾类器官可用作细胞治疗产品。
在根据本发明的用于预防或治疗肾病的药物组合物中,关于Lrig1蛋白或编码Lrig1蛋白之基因、药物组合物、预防、治疗、肾类器官、用于产生肾类器官的方法等的内容与以上在“1.含有肾组织来源干细胞作为活性成分的药物组合物”和“(1)肾类器官”中描述的相同,并因此其的描述将被省略。
本发明的肾类器官可以以选自以下中任一种剂量来施用:1×107至1×108、1×108至2×108、2×108至4×108、4至108至6×108、6×108至8×108、8×108至1×109、1×109至2×109、2×109至4×109、4×109至1×1010、2×108至6×108、6×108至1×109、1×108至2×108、2×108至2×109、1×107至1×108、1×108至1×109、1×109至1×1010、和1×107至1×109个细胞/kg,而不限于此。
4.用于检测的组合物、试剂盒和方法
(1)用于检测肾组织来源干细胞的组合物
本发明的另一个实施方案提供了用于检测肾组织来源干细胞的组合物。
根据本发明的用于检测的组合物含有用于测量Lrig1蛋白的表达水平或测量编码Lrig1蛋白之基因的表达水平的物质。
另外,根据本发明的用于检测的组合物还可含有用于测量Klf6蛋白的表达水平或测量编码Klf6蛋白之基因的表达水平的物质。
在根据本发明的用于检测的组合物中,关于Lrig1或Klf6蛋白以及肾组织来源干细胞的内容与在“1含有肾组织来源干细胞作为活性成分的药物组合物”中所述的那些相同,并因此其的描述将被省略。
在本发明中,用于测量基因表达水平的物质可以是能够测量生物样品中存在的DNA或由其转录的mRNA的表达水平的任何物质。例如,所述物质可以是选自与所述基因特异性结合的引物、探针和反义寡核苷酸中的至少一种,而不限于此。
在本发明中,“引物”是识别靶基因序列的片段,并包含一对正向引物和反向引物,但优选是提供具有特异性和灵敏度的分析结果的一对引物。当引物的核酸序列是与样品中存在的非靶标序列不一致的序列,并因此是仅扩增含有互补引物结合位点的靶基因序列而没有诱导非特异性扩增的引物时,可授予高特异性。
在本发明中,“探针”是指能够与样品中待检测的靶物质特异性结合的物质,其是能够通过结合特异性地检测样品中靶物质的存在的物质。探针的类型不受特别限制,只要其是本领域通常使用的。优选地,探针可以是PNA(peptide nucleic acid,肽核酸)、LNA(locked nucleic acid,锁核酸)、肽、多肽、蛋白质、RNA或DNA,并且最优选PNA。更具体地,探针是来源于生物体或其类似物的生物分子,或者是体外产生的生物分子。探针的一些实例包括酶、蛋白质、抗体、微生物、动物和/或植物细胞和器官、神经元、DNA和RNA。DNA的一些实例包括cDNA、基因组DNA和寡核苷酸,RNA的一些实例包括基因组RNA、mRNA和寡核苷酸,并且蛋白质的一些实例包括抗体、抗原、酶、肽等。
在本发明中,“LNA(锁核酸)”是指含有2’-O或4’-C亚甲基桥的核酸类似物。LNA核苷包含DNA和RNA的共同碱基,并且可以根据沃森-克里克(Watson-Crick)碱基对规则形成碱基对。然而,由于由亚甲基桥引起的分子的“锁定”,LNA无法在沃森-克里克键中形成理想的形状。当LNA被并入DNA或RNA寡核苷酸时,其可以更快地与互补核苷酸链配对,从而提高双链的稳定性。
在本发明中,“反义”意指具有亚基之间的核苷酸序列和主链的寡聚物,其中反义寡聚物通过沃森-克里克碱基配对与RNA中的靶序列杂交以通常允许形成mRNA和RNA:靶序列中的寡聚体异二聚体。寡聚物可与靶序列具有准确或近似的序列互补性。
由于本领域技术人员可以通过NCBI登记号从可用的网站容易地鉴定关于本发明基因的信息,所以本领域技术人员可以基于所鉴定的基因序列容易地构建与所述基因特异性结合的引物、探针或反义核苷酸。
在本发明中,用于测量蛋白质表达水平的物质可以是能够测量生物样品中存在的蛋白质的量的任何物质。例如,物质可以是选自与所述蛋白质特异性结合的抗体、寡肽、配体、肽核酸(PNA)和适配体中的至少一种,而不限于此。
在本发明中,“蛋白质”意指不仅包括蛋白质本身,还包括可以通过剪接和可变启动子产生的或者由于基因改变(例如突变或多态性)产生的蛋白质亚型或蛋白质变体。
在本发明中,“抗体”是指与抗原特异性结合并引起抗原-抗体反应的物质。出于本发明的目的,抗体是指与生物标志物蛋白特异性结合的抗体。本发明的抗体的一些实例包括所有多克隆抗体、单克隆抗体和重组抗体。使用本领域公知的技术可以容易地产生抗体。例如,多克隆抗体可以通过本领域公知的方法产生,该方法包括通过将生物标志物蛋白的抗原注射到动物中并从动物收集血液来获得含有抗体的血清的过程。该多克隆抗体可从任何动物(例如山羊、兔、绵羊、猴、马、猪、牛、狗等)中产生。另外,单克隆抗体可使用本领域公知的杂交瘤方法或噬菌体抗体文库技术产生。通过以上方法产生的抗体可以使用方法(例如凝胶电泳、透析、盐沉淀、离子交换层析或亲和层析)来分离和纯化。另外,本发明的抗体的一些实例不仅包括具有两条全长轻链和两条全长重链的完整形式,而且还包括抗体分子的功能片段。“抗体分子的功能片段”是指至少具有抗原结合功能的片段,并且其一些实例包括Fab、F(ab’)、F(ab’)2和Fv。
在本发明中,“PNA”是指人工合成的DNA或RNA样聚合物,其由丹麦哥本哈根大学的Nielsen、Egholm、Berg和Buchardt教授于1991年首次提出。DNA具有磷酸核糖糖骨架,但PNA具有经由肽键连接的重复的N-(2-氨基乙基)-甘氨酸骨架,并因此具有显著提高的DNA或RNA的结合亲和力和显著提高的稳定性。因此,PNA可用于分子生物学、诊断测定和反义治疗。PNA可参考本发明所属领域中广泛已知的背景技术来进一步详细说明。
在本发明中,“适配体”是寡核苷酸或肽分子,并且关于适配体的一般性内容可以参考以下文献来详细说明:
[Bock LC et al.,Nature 355(6360):5646(1992);Hoppe-Seyler F,Butz K″Peptide aptamers:powerful new tools for molecular medicine″.J Mol Med.78(8):42630(2000);Cohen BA,Colas P,Brent R.″Anartificial cell-cycle inhibitorisolated from a combinatorial library″.Proc Natl Acad Sci USA.95(24):142727(1998)]。
本发明的抗体、寡肽、配体、PNA、适配体等可由本领域技术人员基于通过NCBI登记号从可用的网站可鉴定的氨基酸序列容易地产生。
(2)用于检测肾组织来源干细胞的试剂盒
本发明的另一个实施方案提供了用于检测肾组织来源干细胞的试剂盒,所述试剂盒包含根据本发明的用于检测的组合物。
在本发明的试剂盒中,关于Lrigl蛋白或编码Lrig1蛋白之基因、肾组织来源干细胞、用于测量蛋白表达水平的物质、用于测量基因表达水平的物质等的内容与以上在“1.含有肾组织来源干细胞作为活性成分的药物组合物”和“(1)用于检测肾组织来源干细胞的组合物”中描述的相同,并因此其的描述将被省略。
本发明的试剂盒可以是RT-PCR试剂盒、DNA芯片试剂盒、ELISA试剂盒、蛋白质芯片试剂盒、快速试剂盒或多反应监测(multiple reaction monitoring,MRM)试剂盒,而不限于此。
本发明的试剂盒还可包含一种或更多种适合于所述测定方法的另外的组分组合物、溶液或装置。
在本发明的一个实施方案中,试剂盒还可包含用于进行逆转录聚合酶反应所需的必要元素。逆转录聚合酶反应试剂盒包含一对对基因具有特异性的引物。引物是具有对基因的核酸序列具有特异性的序列的寡核苷酸,并且长度可以为约7bp至50bp(更优选约10bp至30bp)。试剂盒还可包含对对照基因(例如管家基因)的核酸序列具有特异性的引物。另外,逆转录聚合酶反应试剂盒可包含试管或另外的合适的容器、反应缓冲液(多种pH和镁浓度)、脱氧核苷酸(dNTP)、酶(例如Taq聚合酶和逆转录酶)、DNA酶、RNA酶抑制剂、DEPC-水、无菌水等,而不限于此。
在本发明的另一个实施方案中,本发明的诊断试剂盒可包含进行DNA芯片测定所需的必需元素。DNA芯片试剂盒可包含其上已固定有对应于基因或其片段的cDNA或寡核苷酸的基质、用于构建荧光标记的探针的试剂、物质、酶等。另外,基质可包含对应于对照基因(例如管家基因)或其片段的cDNA或寡核苷酸,而不限于此。
在本发明的另一个实施方案中,本发明的诊断试剂盒可包含进行ELISA所需的必要元素。ELISA试剂盒包含对蛋白质具有特异性的抗体。抗体对标志物蛋白具有高特异性和亲和力,并且表现出与其他蛋白质有极小的或没有交叉反应性。其是单克隆抗体、多克隆抗体或重组抗体。ELISA试剂盒还可包含对对照蛋白(例如管家蛋白)具有特异性的抗体。另外,ELISA试剂盒可包含能够检测结合抗体的试剂,例如经标记的二抗、发色团、酶(例如,与抗体缀合的酶)及其基质或能够与抗体结合的另外的物质。
(3)用于检测肾组织来源干细胞的方法
本发明的另一个实施方案提供了用于检测肾组织来源干细胞的方法。
根据本发明的用于检测的方法包括测量来自从目的对象分离的生物样品的Lrig1蛋白的表达水平或编码Lrig1蛋白之基因的表达水平的步骤。
另外,在本发明中,在测量表达水平的步骤中,还可测量来自生物样品的Klf6蛋白的表达水平或编码Klf6蛋白之基因的表达水平。
在根据本发明的用于检测的方法中,关于肾组织来源干细胞、Lrig1或Klf6蛋白或编码其的基因等的内容与以上在“1.含有肾组织来源干细胞作为活性成分的药物组合物”和“(1)用于检测肾组织来源干细胞的组合物”中描述的相同,并因此其描述将被省略。
在本发明中,“生物样品”是指从个体中获得的或来源于个体的任何物质、生物流体、组织或细胞,并且可包括例如血液(包括全血、白细胞、外周血单个核细胞、血沉棕黄层、血浆和血清)、尿、精液、器官分泌物、细胞或细胞提取物,并且可以是例如肾组织或肾细胞,而不限于此。
在本发明中,测量基因表达水平的步骤可以通过逆转录聚合酶反应(RT-PCR)、竞争性RT-PCR、实时RT-PCR、RNA酶保护测定(RNase protection assay,RPA)、Northern印迹、DNA芯片测定等通过使用用于测量基因表达水平的物质来进行,所述试剂是选自与基因特异性结合的引物、探针和反义寡核苷酸中的至少一种,而不限于此。
在本发明中,测量蛋白质表达水平的步骤可通过以下通过使用用于测量蛋白质表达水平的物质来进行:蛋白质芯片分析、免疫测定、配体结合测定、MALDI-TOF(基质辅助激光解吸/电离飞行时间质谱)分析、SELDI-TOF(表面增强激光解吸/电离飞行时间质谱)测定、辐射免疫测定、辐射免疫扩散、Ouchterlony免疫扩散、火箭免疫电泳、组织免疫染色、补体固定测定、2D电泳测定、液相色谱-质谱(liquid chromatography-mass spectrometry,LC-MS)、液相色谱-质谱/质谱(liquid chromatography-mass spectrometry/massspectrometry,LC-MS/MS)、Western印迹和酶联免疫吸附测定(enzyme-linkedimmunosorbent assay,ELISA),所述试剂是选自与蛋白质特异性结合的抗体、寡肽、配体、肽核酸(PNA)和适配体中的至少一种,而不限于此。
根据本发明的用于检测的方法还可包括将以下细胞检测为肾组织来源干细胞的步骤:在所述细胞中Lrig1蛋白的表达水平或编码Lrig1蛋白之基因的表达水平比对照组更高。
5.用于分离肾组织来源干细胞的方法
本发明的另一个实施方案提供了用于分离肾组织来源干细胞的方法。
根据本发明的用于分离的方法包括从分离自目的对象的生物样品分离表达Lrigl蛋白的细胞或表达编码Lrigl蛋白之基因的细胞的步骤。
在本发明中,分离细胞的步骤中的细胞还可表达Klf6蛋白或表达编码Klf6蛋白之基因。
在根据本发明的用于分离的方法中,关于Lrig1或Klf6蛋白或编码其的基因、肾组织来源干细胞、生物样品等的内容与以上在“1.含有肾组织来源干细胞作为活性成分的药物组合物”、“(1)用于检测肾组织来源干细胞的组合物”和“(3)用于检测肾组织来源干细胞的方法”中描述的相同,并因此其的描述将被省略。
在本发明中,分离的步骤可通过磁性活化细胞分选(MACS)或流式细胞术分析来进行。
6.用于培养肾组织来源干细胞的方法
本发明的另一个实施方案提供了用于培养肾组织来源干细胞的方法。
根据本发明的用于培养的方法包括以下步骤:分离表达Lrig1蛋白的肾组织来源干细胞或分离表达编码Lrig1蛋白之基因的肾组织来源干细胞;以及培养所分离的肾组织来源干细胞。
在本发明中,分离步骤中的肾组织来源干细胞还可表达Klf6蛋白或表达编码Klf6蛋白之基因。
在根据本发明的用于分离的方法中,关于Lrig1或Klf6蛋白或编码其的基因、肾组织来源干细胞等的内容与以上在“1.含有肾组织来源干细胞作为活性成分的药物组合物”中描述的相同,并因此其的描述将被省略。
根据本发明的用于培养的方法可包括根据本文中在“5.用于分离肾组织来源干细胞的方法”中描述的方法分离肾组织来源干细胞,并随后将其例如在体外培养,而不限于此。
根据本发明的培养的步骤中的“培养”意指细胞的任何体外培养。本发明中的培养可使用细胞培养基来进行,并且细胞培养基是指在细胞培养环境中使用的任何类型的培养基,并且可含有例如氨基酸、至少一种碳水化合物作为能量来源、微量元素、维生素、盐和可能的另外的成分(例如,以影响细胞生长、生产力或产物质量),而不限于此。
7.用于产生动物模型的方法
本发明的另一个实施方案提供了用于产生动物模型的方法,所述动物模型用于筛选用于预防或治疗肾病的细胞治疗产品。
根据本发明的用于产生动物模型的方法包括以下步骤:在其中通过CreERT2-LoxP系统目的基因条件性表达的动物中诱导肾损伤;以及通过用雌激素拮抗剂处理来诱导动物中目的基因的表达。
在根据本发明的用于产生动物模型的方法中,关于肾组织来源干细胞、肾病和细胞治疗产品的内容与以上在“1.含有肾组织来源干细胞作为活性成分的药物组合物”中描述的相同,并因此其的描述将被省略。
在本发明中,“CreERT2-LoxP系统”是指这样的系统:其中启动子特异性表达的Cre-ERT2多肽识别两个LoxP核苷酸序列并催化两个LoxP核苷酸序列之间的位点特异性重组,从而特异性表达LoxP核苷酸序列的下游基因。根据在Lab Anim Res.Dec 2018;34(4):147-159中描述的内容,本领域技术人员可以容易地进行构建该系统的方法。
在本发明中,“目的基因”是指在具有用作细胞治疗产品的潜力的细胞中特异性表达或预期将要表达的基因。出于本发明的目的,“目的基因”可以是编码Lrig1的基因,优选编码Lrig1的基因和编码Klf6的基因,而不限于此。
在本发明中,“动物模型”是指可以表现出与人疾病等非常相似的疾病形式的动物。当使用该动物模型时,可以研究多种疾病的病因和发病机理,并获得用于确定可能性(例如治疗剂的选择或毒性测试的进行)的基础数据。
本发明中的术语“动物”是指任何非人哺乳动物,并且包括所有年龄的动物,包括胚胎、胎儿、新生儿和成体。该动物可以是选自以下中的任一种:兔、啮齿动物(例如,小鼠、大鼠、仓鼠、沙鼠或豚鼠)、牛、绵羊、猪、山羊、马、狗、猫、鸟(例如,鸡、火鸡、鸭或鹅)和灵长类(例如黑猩猩、猴或恒河猴),而不限于此。
在本发明中,诱导肾损伤的步骤可以通过选自腹膜内施用叶酸、诱导缺血/再灌注损伤和诱导单侧输尿管梗阻中的任一种来进行,而不限于此。
在本发明中,叶酸可以以100mg/kg至300mg/kg(例如150mg/kg或250mg/kg)的剂量腹膜内施用,而不限于此。如果叶酸的剂量低于100mg/kg,则可能不会在肾中诱导急性肾损伤,并且如果剂量超过300mg/kg,则其可在动物模型中引起毒性,影响所期望实验结果的解读或导致动物模型的死亡。
本发明中的雌激素拮抗剂可以是他莫昔芬、4-羟基他莫昔芬、氯米芬(clomifen)、雷洛昔芬(raloxifene)、或其组合,而不限于此。
8.动物模型
本发明的另一个实施方案提供了通过本发明的产生方法产生的用于筛选用于预防或治疗肾病的细胞治疗产品的动物模型。
在本发明的动物模型中,关于产生方法、细胞治疗产品、肾病等的内容与以上在“1.含有肾组织来源干细胞作为活性成分的药物组合物”和“6.用于产生动物模型的方法”中描述的相同,并因此其的描述将被省略。
有益效果
根据本发明的肾组织来源干细胞或类器官易于应用于治疗、由于其高自我更新能力而可以大量供应、具有优异的分化成肾细胞的能力、不太可能形成肿瘤、并且具有优异的当直接注射到病灶中时使受损组织再生的能力。因此,它们可以非常适合用于基于特别是这些干细胞中成体干细胞的再生治疗。
另外,根据本发明的组合物能够在肾细胞中特异性地仅选择肾组织来源干细胞。此外,表达Lrig1蛋白的肾组织来源干细胞或表达编码Lrig1蛋白之基因的肾组织来源干细胞具有优异的自我更新和多能性能力,并能够分化成肾单位,并因此它们可以非常有效地用于预防或治疗肾病。
附图说明
图1是示出根据本发明的实例在体内谱系追踪研究中使用小鼠动物模型进行的实验过程的示意图。
图2是示出根据本发明的实例在体内谱系追踪研究中使用胚胎小鼠动物模型进行的实验过程的示意图。
图3是示出根据本发明的实例用于产生高剂量(250mg/kg)叶酸诱导的急性肾损伤的动物模型的方法的示意图。
图4是示出根据本发明的实例将本发明的肾类器官移植到高剂量(150mg/kg)叶酸诱导的急性肾损伤的动物模型中,并随后进行分析的过程的示意图。
图5是示出根据本发明的实例用于产生缺血/再灌注损伤诱导的急性肾损伤的动物模型的方法的示意图。
图6是示出根据本发明的实例用于产生单侧输尿管梗阻诱导的急性肾损伤的动物模型的方法的示意图。
图7示出了根据本发明的实例通过组织染色确认小鼠肾中存在或不存在tdTomato+细胞(Lrig1tdT+)的结果。
图8示出了根据本发明的实例量化小鼠肾中tdTomato+细胞(Lrig1tdT+)的数量的结果。
图9示出了根据本发明的实例通过组织染色确认处于发育阶段的小鼠中存在或不存在tdTomato+细胞(Lrig1tdT+)的结果。
图10示出了根据本发明的实例量化处于发育阶段的小鼠中tdTomato+细胞(Lrig1tdT+)的数量的结果。
图11示出了根据本发明的实例使用荧光显微镜观察肾类器官的结果。
图12示出了根据本发明的实例通过实时聚合酶链式反应分析在肾类器官中表达的基因的表达水平的结果。
图13示出了根据本发明的实例,表明当从第1天至第19天长时间培养肾类器官时,肾类器官的数量增加的结果。
图14示出了根据本发明的实例,在将PBS或本发明的肾类器官移植到高剂量(150mg/kg)叶酸诱导的急性肾损伤的动物模型中之后,进行组织染色和分析KIM1的表达水平以确认肾修复的结果。
图15示出了根据本发明的实例,在将PBS或本发明的肾类器官移植到高剂量(150mg/kg)叶酸诱导的急性肾损伤的动物模型中之后,分析血液BUN和肌酐浓度以确认肾修复的结果。
图16示出了根据本发明的实例通过荧光显微术分析肾类器官中Ki-67表达的结果。
图17示出了根据本发明的实例,将在肾类器官中的近端小管(PT)簇分类成四个亚簇(PTS1、PTS2、PTS3和PTQP)的结果。
图18和19是示出根据本发明的实例,分析在肾类器官中在PTS1、PTS2、PTS3和PTQP簇的每一者中的基因表达水平的结果的气泡图。
图20示出了根据本发明的实例,在肾类器官移植之后在Cre-loxp诱导之后在第1天和第365天测量PTS1、PTS2、PTS3和PTQP簇细胞的百分比的结果。
图21示出了根据本发明的实例,在肾类器官移植之后在Cre-loxp诱导之后,测量与第1天相比,在第365天PTS1、PTS2、PTS3和PTQP簇细胞的数量变化的结果。
图22描绘了根据本发明的实例,示出分析在肾类器官中PTS1、PTS2、PTS3和PTQP簇的每一者中自我更新相关基因、静止(quiescence)相关基因和多能/未成熟细胞相关基因的表达水平的结果的小提琴图。
图23示出了根据本发明的实例,在肾类器官中在PTS3和PTQP簇的每一者中高度表达的前10个基因。
图24示出了根据本发明的实例,在肾类器官移植之后在Cre-loxp诱导之后在第1天和第365天,肾切片中LTL(PT标志物)和KLF6的免疫荧光染色图像。
图25示出了根据本发明的实例,在肾类器官移植之后在Cre-loxp诱导之后在第1天和第365天,量化肾切片中每20×视野的LTL+KLF6+细胞的结果(N=3;24个图像)。
图26示出了根据本发明的实例,在肾类器官移植之后在Cre-loxp诱导之后在第1天和第365天在每个簇中tdTomato+细胞的百分比。
图27示出了根据本发明的实例,将肾类器官的近端小管(PT)中的拟时间谱系分类成三种不同状态的结果。在此,PTS1、PTS3和PTQP簇由不同的颜色指示,并且黑色箭头指示拟时间的方向。
图28示出了根据本发明的实施方案,在肾类器官移植之后在Cre-loxp诱导之后在第1天和第365天,在系统发育图上绘制tdTomato+细胞的结果,以及绘制代表颜色编码表达水平的热图的结果。在此,低表达以灰色示出,并且高表达以红色示出。
图29示出了根据本发明的实例,在肾类器官移植之后在Cre-loxp诱导之后在第1天和第365天,肾切片中Lrig1tdTomato+和KLF6染色的免疫荧光染色图像。
图30示出了根据本发明的实例,在肾类器官移植之后在Cre-loxp诱导之后在第1天和第365天,量化肾切片中每20×视野的Lrig1tdTomato+KLF6+细胞的结果(N=5;42个图像)。
最佳实施方式
本发明旨在克服肾病(例如急性肾衰竭)的常规治疗的局限性,并旨在开发更有效的治疗剂。本发明旨在使用肾组织来源干细胞或类器官来开发用于肾病的有效治疗剂。在仅用高浓度叶酸(folic acid,FA)处理的情况下和用高浓度叶酸和PBS注射(FA+PBS)处理的情况下,血液BUN和肌酐水平非常高,然而当注射肾类器官时,血液BUN和肌酐水平降低至与正常水平相似的水平。这些结果直接表明Lrig1阳性的肾类器官可非常有效地用于治疗受损的肾。
具体实施方式
[实验方法]
[实验方法1]实验动物
在本说明书中进行的所有体内实验均经延世大学机构动物护理和使用委员会(IACUC 2017-0325)批准。
实验动物在12小时交替光暗循环下被饲养在无特定病原体的(specificpathogen-free,SPF)屏障设施中,并通过喂养PicoLab Lab Rodent Diet 20(LabDiet,St.Louis,MO,USA)来饲养。
对于在体内实验中使用的实验动物,1)Lrig1CreERT2/+由范德比尔特大学的Robert J.Coffey提供,2)B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato)/Hze/J(R26R-LSL-tdTomato;The Jackson Laboratory,007914)由延世大学的Bok Jin-Woong教授提供,以及3)B6.129(Cg)-Gt(ROSA)26Sortm4(ACTB-tdToamto-EGFP)Luo/J(ACTB-mT/mG;The JacksonLaboratory,007676)由延世大学的Hyun-Woong Ki教授提供。
[实验方法2]用于体内谱系追踪研究的方法
如图1中所示,杂合小鼠通过使以上实验方法1中所描述的Lrig1CreERT2/+小鼠与R26R-LSL-tdTomato小鼠(纯合报道小鼠)交配产生。向小鼠注射包含在玉米油中的2mg他莫昔芬(Sigma-Aldrich)到腹腔中连续3天,以诱导Cre-loxp重组,并随后在第1天、3天、10天、30天、60天、90天、180天或365天进行分析。
另外,如图2中所示,将包含在玉米油中的2mg 4-羟基他莫昔芬(Sigma-Aldrich)一次注射到由Lrig1CreERT2/+小鼠与R26R-LSL-tdTomato小鼠(纯合报道小鼠)交配产生的E9.5、E10.5、E13.5和E18.5胚胎中,并在出生之后6周进行分析。
[实验方法3]体外2D和类器官培养方法
对于2D和类器官培养,将通过使Lrig1CreERT2/+小鼠与R26R-ACTB-mT/mG小鼠交配产生的纯合报道小鼠饲养6至10周,并随后从中收集原代肾上皮细胞。将2mg/ml的1型胶原酶添加至收集的原代肾上皮细胞,并在37℃下轻度搅拌培养30分钟。此后,将原代肾上皮细胞通过过滤器过滤,并随后培养分离的单一细胞。接下来,将表达Lrig1蛋白的细胞添加至RPMI 1640培养基(含有10%胎牛血清(fetal bovine serum,FBS)、20ng/ml EGF和1%青霉素-链霉素),并在37℃下、在5%CO2下培养至约80%的汇合,持续7至8天。此后,将经培养的细胞以1×103个细胞/孔的密度分配到含有生长因子减少的基质胶和培养基的孔中并培养。在此使用的培养基是基于含有1%青霉素-链霉素、HEPS和Glutamax的ADMEM/F12培养基,并含有1.5% B27补充剂、40% Wnt3a条件培养基(使用稳定转染的L细胞产生的)、10%Noggin条件培养基、10% Rspo1条件培养基、50ng/ml EGF、100ng/mL FGF-10、1.25mM N-乙酰半胱氨酸和5μM A8301(CAS号909910-43-6)。
在细胞在基质胶中充分聚合之后,添加类器官培养基,并每3天更换类器官培养基。
[实验方法4]急性肾损伤动物模型的构建
[4-1]高剂量叶酸诱导的急性肾损伤的动物模型的构建
如图3中所示,将他莫昔芬注射到如实验方法2中所描述的成年(8至10周龄)Lrig1-CreERT2、LSL-tdTomato小鼠中使得Lrig1蛋白可以表达。然后,腹膜内注射250mg/kg叶酸(FA)以诱导急性肾损伤。
另外,如图4中所示,将150mg/kg叶酸腹膜内注射到C57BL/6小鼠中以诱导急性肾损伤,并在叶酸注射之后第3天,将在实验方法3中产生的肾类器官原位移植。具体地,将诱导急性肾损伤的C57BL/6小鼠(n=3)使用异氟烷麻醉,并通过切开胁腹将肾暴露于外部。然后,将作为对照的PBS或在以上实验方法3中产生的约40个肾类器官直接注射到肾的皮质区中至少15次。然后,将小鼠饲养11天用于分析。然后,在第14天,从小鼠中取样血液以测量血浆肌酐和BUN水平。
[4-2]缺血/再灌注损伤诱导的急性肾损伤的动物模型的构建
如图5中所示,将他莫昔芬注射到如实验方法2中所描述的成年(8至10周龄)Lrig1-CreERT2、LSL-tdTomato小鼠中使得可以表达Lrig1蛋白。然后,通过用钳子(forcep)使小鼠肾动脉闭塞20分钟来诱导急性肾损伤。在3天之后,作为从小鼠中收集和分析肾组织的结果,可以确认诱导了急性肾损伤。
[4-3]单侧输尿管梗阻诱导的急性肾损伤的动物模型的构建
如图6中所示,将他莫昔芬注射到如实验方法2中所描述的成体(8至10周龄)Lrig1-CreERT2、LSL-tdTomato小鼠中使得可以表达Lrig1蛋白。然后,通过用钳使输尿管闭塞7天来诱导急性肾损伤。在7天之后,作为从小鼠中收集和分析肾组织的结果,确认诱导了急性肾损伤。
[实验结果]
[实验结果1]通过他莫昔芬在小鼠肾中诱导Lrig1-tdTomato后代的系谱分析
为了分析肾中表达Lrig1的细胞及其后代的行为,使用R26R-LSL-tdTomato小鼠模型进行谱系追踪分析。
如图7中所示,确认了:在第1天,在皮质中观察到非常低水平的tdTomato+细胞,而在第365天,由表达Lrig1的细胞产生的后代细胞在整个肾的12%(±2.4%)中形成管状结构。
如图8中所示,当表达Lrig1的细胞(Lrig1tdT+)的数量被量化为时间(天)的函数时,确认了这些细胞克隆随着时间的推移逐渐增加,并且这种增加在Lrig1表达之后持续多至365天。
如图9和10中所示,在输尿管芽分支期(E9.5和E10.5)时没有观察到tdTomato+细胞(Lrig1tdT+)。然而,在E13.5(肾发生期)时,观察到tdTomato+细胞,并且大多数所述细胞扩增以形成管状结构。
从这些结果可以看出,表达Lrig1的细胞是在最初发育为成熟肾之后参与肾单位分化的干细胞群。
[实验结果2]在由高浓度叶酸诱导的急性肾损伤的动物模型中通过肾类器官的原位移植的治疗效果的确认
如图11所示中,作为使用荧光显微镜分析通过在实验方法3中所描述的方法产生的肾类器官的结果,在培养该肾类器官之后的第7天和第9天观察到大量绿色Lrig1细胞。
另外,如图12中所示,作为在培养该肾类器官之后第17天根据常规方法使用下表1中所示的引物通过实时PCR分析基因表达水平的结果,确认了不仅Lrig1的表达水平提高,而且肾干细胞基因(例如Sall1、Six2、Foxo1、Cited、Osr1、Hoxp7、Jagged1和Gata3)的表达水平也提高。此外,如图13中所示,在Lrig1阳性肾类器官的情况下,从第9天至第19天,产生的类器官的数量提高至约40个或更多。
[表1]
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如图14中所示,根据实验方法4的方法,将PBS(FA+PBS)或肾类器官(FA+类器官)直接注射到在以上实验方法4的[4-1]中所描述的由高浓度叶酸诱导的急性肾损伤的动物模型的肾中,并在14天之后,根据常规方法进行H&E染色。作为结果,确认了当仅注射PBS(FA+PBS)时,由高浓度叶酸损伤的肾未被修复,并且KIM1的表达水平是高的,而当注射肾类器官时,由高浓度叶酸损伤的肾被修复,并且KIM1的表达水平降低。从这些结果可以看出,注射肾类器官可以非常有效地修复损伤的肾。
另外,如图15中所示,当将肾仅用高浓度叶酸(FA)处理时或者和当将肾用高浓度叶酸处理并注射了PBS(FA+PBS)时,血液BUN和肌酐水平非常高,而当注射肾类器官时,血液BUN和肌酐水平降低至与正常水平相似的水平。这些结果直接表明Lrig1阳性的肾类器官可以非常有效地用于治疗受损的肾。
另外,如图16中所示,作为通过荧光显微镜观察的结果,注射到肾中的类器官被确认免疫荧光染色,并且可以看出表达了增殖标志物(例如Ki-67),表明注射到肾中的类器官是增殖性的。
[实验结果3]Lrig1阳性细胞及其后代对成体肾中干细胞生态位形成的作用
从先前的实验结果可以看出,Lrig1阳性细胞在近端小管(PT)中存活很长时间,并对应于潜在的肾干/祖细胞,并且来自Lrig1阳性细胞的后代显著促进了维持PT稳态。为了确认Lrig1+细胞及其后代在PT中的细胞异质性,如图17中所示,将PT簇分成四个亚簇:PTS1、PTS2、PTS3和PTQP。此时,Slc5a12和Slc5a2标志物用于PTS1类别,Slc13a3和Ddah1标志物用于PTS2类别,并且Slc16a9和Slc7a13标志物用于PTS3类别。另外,如图18中所示,本发明人发现了大量表达丙酮酸脱氢酶肾4(Pyruvate dehydrogenase kidney 4,Pdk4)和富含半胱氨酸蛋白61(Cysteine-rich protein 61,Cyr61)(其在急性肾损伤病症中上调)的亚簇PTQP。为了更具体的限定,将PTQP与另外的PT亚簇进行比较。作为分析PTQP中表达的前50种基因的表达水平的结果,如图19中所示,可确认与肾损伤和修复相关的基因在PTQP中高度表达,并且2种肾单位祖基因也在其中表达。如图20中所示,作为测量每个PT亚簇中的细胞数量的结果,确认了在Cre-loxp重组之后的第365天,PTS2和PTQP细胞的数量增加。另外,如图21中所示,可确认在Cre-loxp重组之后在第365天,肾中的PTQP亚簇细胞的数量是第1天肾中的那些的5倍高。这表明PT细胞的数量随时间而增加,并且特别是PTQP和PTS2簇细胞的数量增加。接下来,本发明人使用成体干细胞基因模块限定了肾中的PTQP亚簇。因此,在DEG中总共检测到650种基因。如图22中所示,可确认干性相关的基因在PTQP簇中高度表达,并且自我更新相关的基因(Ptbp1、Ncl、Ctr9和Cited2,不包括Klf5)、静止相关的基因(Hif1a、Myc和Foxo3)和多能或未成熟细胞相关的基因(Id2、Btg2、Tubb6和Klf2)上调。这表明PTQP亚簇表达干性相关的基因,包括与肾损伤修复相关的基因和成熟PT细胞的标志物。基于这些结果,相应的亚簇被命名为“PT静止祖细胞(PT quiescent progenitor,PTQP)”。
接下来,作为鉴定与PTS3不同的PTQP的标志物的结果,如图23所示,可以鉴定出在DEG中高度表达的被称为干细胞生态位的基因。PT区段3特异性基因在PTS3亚簇中高度表达,而在PTQP中不高度表达。为了验证PTQP标志物,使用Jun、Klf6和Cyr61对肾切片进行IF染色。Jun和Cyr61被排除,因为它们不仅在PT中高度表达,而且还在多种肾单位区段中高度表达。接下来,对第1天和第365天的肾切片中染色的KLF6和LTL进行染色以确认它们是否被表达。如图24中所示,Klf6+LTL+PT小管在第1天在肾切片中弱表达,而Klf6+LTL+PT小管在第365天在肾切片中强表达。作为量化的结果,如图25中所示,可确认在第365天肾中表达KLF6+的PT小管显著增加。这表明使用Klf6可确认在第365天肾中PTQP的分布提高。
为了确认来自Lrig1阳性细胞的后代是否形成PTQP群体,本发明人检查了第1天和第365天肾切片中表达tdTomato的细胞。作为结果,如图26中所示,在第1天肾切片中tdTomato+细胞占PTS1细胞的54%并占PTS3细胞的27%,然而,在第365天在肾切片中,其分别下降至50%和11%。另一方面,在第1天肾切片中tdTomato+细胞占PTS2细胞的12%并占PTQP细胞的17.8%,然而,其在第365天分别提高至20%和18%。这表明来自Lrig1阳性细胞的后代形成了PTQP群体。另外,通过单一细胞上的信息分析了显示向分化进展的细胞轨迹。轨迹的初始阶段对应于被称为PT干细胞生态位的PTS3和被鉴定作为新干细胞生态位的PTQP。该细胞群可分成朝向PTS1的两种不同的轨迹(图27)。可以看出,在第1天在肾中,PTS3占优势并随后分化为PTS1亚簇,并且在第365天,PTQP簇主要进行主要是PTS1亚簇的细胞稳态。作为在第1天和第365天将在PTS3和PTQP的情况下的表达tdTomato的细胞进行比对的结果,如图28中所示,可以确认,在第1天,在PTS3簇中表达tdTomato的细胞分化为PTS1,并且在第365天,在PTQP簇中表达tdTomato的细胞主要维持PTS1。作为对Klf6和tdTomato+细胞进行染色的结果,如图29和30中所示,可以确认,与第1天相比,Klf6+tdTomato+小管在第365天显著增加。这表明Lrig1阳性细胞及其后代形成了PTQP簇。即使在实验条件下,第1天的肾取自6周龄的小鼠,而第365天的肾取自13月龄的小鼠。从上述实验结果可以看出,发现在幼龄肾(第一天的肾)中肾稳态通过PTS3调节,并且PTQP在老龄肾(第365天的肾)中显示出新的干细胞生态位。
尽管已经详细描述了本发明,但是本发明的范围不限于本说明书,并且对于本领域的技术人员来说将明显的是,在不脱离如权利要求中阐述的本发明的技术精神的情况下,多种修改和变更是可能的。
工业适用性
本发明旨在克服肾病(例如急性肾衰竭)的常规治疗的局限性,并旨在开发更有效的治疗剂。目前,关于肾干细胞的鉴定、将肾干细胞用于作为治疗剂应用的鉴定及其用于临床使用的适用性的研究仍然不足,并且需要开发这样的肾干细胞。根据本发明的肾组织来源干细胞或类器官易于应用于治疗、具有优异的分化成肾细胞的能力、不太可能形成肿瘤、并且具有优异的当直接注射到病灶中时使受损组织再生的能力,并因此它们可以非常有效地用于预防或治疗肾病。
序列表自由文本
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Claims (30)
1.用于预防或治疗肾病的药物组合物,其含有作为活性成分的表达Lrig1(富含亮氨酸重复和免疫球蛋白样结构域1)蛋白的肾组织来源干细胞或表达编码所述Lrig1蛋白之基因的肾组织来源干细胞。
2.权利要求1所述的药物组合物,其中所述肾组织来源干细胞还表达Klf6(Krueppel样因子6)蛋白或表达编码所述Klf6蛋白之基因。
3.权利要求1所述的药物组合物,其中所述肾病是急性肾损伤(AKI)或慢性肾病(CKD)。
4.肾类器官,其包含表达Lrig1蛋白的肾组织来源干细胞或表达编码所述Lrig1蛋白之基因的肾组织来源干细胞。
5.权利要求4所述的肾类器官,其中所述肾组织来源干细胞还表达Klf6(Krueppel样因子6)蛋白或表达编码所述Klf6蛋白之基因。
6.用于预防或治疗肾病的药物组合物,其含有权利要求4或5所述的肾类器官作为活性成分。
7.用于产生肾类器官的方法,其包括以下步骤:
(a)从分离自目的对象的肾上皮细胞分离表达Lrig1(富含亮氨酸重复和免疫球蛋白样结构域1)蛋白的细胞或表达编码所述Lrig1蛋白之基因的细胞;
(b)培养表达所述Lrig1蛋白的细胞或表达编码所述Lrig1蛋白之基因的细胞;以及
(c)由在基质胶中培养的细胞形成类器官。
8.权利要求7所述的方法,其中在步骤(a)中分离的所述细胞还表达Klf6(Krueppel样因子6)蛋白或表达编码所述Klf6蛋白之基因。
9.权利要求7所述的方法,其中培养表达所述基因的细胞的步骤(b)是使用含有胎牛血清、生长因子和抗生素的细胞培养基进行的。
10.权利要求7所述的方法,其中形成所述类器官的步骤(c)是使用含有B27补充剂、条件培养基、生长因子、N-乙酰半胱氨酸和ALK 5(TGFβ激酶/激活素受体样激酶)抑制剂的细胞培养基进行的。
11.权利要求10所述的方法,其中所述条件培养基是选自Wnt3a条件培养基、Noggin条件培养基和Rspo1条件培养基中的至少一种。
12.权利要求7所述的方法,其中所述基质胶是生长因子减少的基质胶。
13.用于检测肾组织来源干细胞的组合物,其含有用于测量Lrig1(富含亮氨酸重复和免疫球蛋白样结构域1)蛋白的表达水平或用于测量编码所述Lrig1蛋白之基因的表达水平的物质。
14.权利要求13所述的组合物,其还含有用于测量Klf6(Krueppel样因子6)蛋白的表达水平或用于测量编码所述Klf6蛋白之基因的表达水平的物质。
15.权利要求13所述的组合物,其中所述用于测量所述基因的表达水平的物质是选自与所述基因特异性结合的引物、探针和反义寡核苷酸中的至少一种。
16.权利要求13所述的组合物,其中所述用于测量所述蛋白质的表达水平的物质是选自与所述蛋白质特异性结合的抗体、寡肽、配体、肽核酸(PNA)和适配体中的至少一种。
17.用于检测肾组织来源干细胞的试剂盒,其包含权利要求13至16中任一项所述的组合物。
18.用于检测肾组织来源干细胞的方法,其包括测量来自从目的对象分离的生物样品中的Lrig1(富含亮氨酸重复和免疫球蛋白样结构域1)蛋白或编码所述Lrig1蛋白之基因的表达水平的步骤。
19.权利要求18所述的方法,其中在所述测量所述表达水平的步骤中还测量了来自所述生物样品的Klf6(Krueppel样因子6)蛋白或编码所述Klf6蛋白之基因的表达水平。
20.权利要求18所述的方法,其中所述基因的表达水平是通过选自与所述基因特异性结合的引物、探针和反义寡核苷酸中的至少一种来测量的。
21.权利要求18所述的方法,其中所述蛋白质的表达水平是通过选自与所述蛋白质特异性结合的抗体、寡肽、配体、PNA和适配体中的至少一种来测量的。
22.权利要求18所述的方法,其还包括将以下细胞检测为所述肾组织来源干细胞的步骤:在所述细胞中Lrig1(富含亮氨酸重复和免疫球蛋白样结构域1)蛋白或编码所述Lrig1蛋白之基因的表达水平比对照组更高。
23.用于分离肾组织来源干细胞的方法,其包括从分离自目的对象的生物样品分离表达Lrig1(富含亮氨酸重复和免疫球蛋白样结构域1)蛋白的细胞或分离表达编码所述Lrig1蛋白之基因的细胞的步骤。
24.权利要求23所述的方法,其中所述分离的细胞还表达Klf6(Krueppel样因子6)蛋白或表达编码所述Klf6蛋白之基因。
25.权利要求23所述的方法,其中所述分离的步骤是通过磁性活化细胞分选(MACS)或流式细胞术分析进行的。
26.用于培养肾组织来源干细胞的方法,其包括以下步骤:
分离表达Lrig1(富含亮氨酸重复和免疫球蛋白样结构域1)蛋白的肾组织来源干细胞或分离表达编码所述Lrig1蛋白之基因的肾组织来源干细胞;以及
培养所分离的肾组织来源干细胞。
27.权利要求26所述的方法,其中所分离的细胞还表达Klf6(Krueppel样因子6)蛋白或表达编码所述Klf6蛋白之基因。
28.用于产生筛选预防或治疗肾病的细胞治疗产品的动物模型的方法,所述方法包括:
在动物中诱导肾损伤,在所述动物中编码Lrig1(富含亮氨酸重复和免疫球蛋白样结构域1)的基因由CreERT2-LoxP系统条件性表达;以及
通过用雌激素拮抗剂处理来诱导所述动物中目的基因的表达。
29.权利要求28所述的方法,其中所述诱导肾损伤的步骤是通过选自腹膜内施用叶酸、诱导缺血/再灌注损伤和诱导单侧输尿管梗阻中的任一者来进行的。
30.用于筛选预防或治疗肾病的细胞治疗产品的动物模型,所述动物模型是根据权利要求28所述的方法产生的。
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