CN111278446A - 从骨髓龛提取干细胞 - Google Patents
从骨髓龛提取干细胞 Download PDFInfo
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Abstract
本发明的主题是一种用于将干细胞从骨髓龛可逆地释放到外周血中并分离这些干细胞的方法。此外,本发明涉及以这种方式获得的干细胞及它们在医学治疗中的用途。
Description
本发明的主题是一种用于将干细胞从骨髓龛(bone marrow niches)可逆地释放到外周血中并分离这些干细胞的方法。此外,本发明涉及以这种方式获得的干细胞及它们在医学治疗中的用途。
造血干细胞是通过造血过程产生所有其他血细胞的干细胞。发现它们存在于骨髓中,尤其是在骨盆、股骨和胸骨中,在外周血中也少量存在。为了提取用于医学目的的造血干细胞,可以从骨髓收获它们。作为一种可替代技术,造血干细胞通常通过称为单采血液分离术(清血法)的过程从外周血获得。由于血液中干细胞的数量通常太少而无法获得大量的它们,所以有必要从它们起源部位将干细胞动员到循环中并增加外周血中干细胞的数量,从而允许更有效地从血液循环收集增加量的干细胞。例如,这可以通过诱导细胞离开骨髓并在血管中循环的细胞因子来完成,诸如粒细胞集落刺激因子(G-CSF)和粒细胞巨噬细胞集落刺激因子(GM-CSF)。能够将干细胞动员到受试者的循环血液中的因子和剂的其他实例是CXCR4-受体抑制剂,诸如MozobilTM。
国际申请WO 2008/019371描述了G-CSF与至少一种CXCR4抑制剂和至少一种CXCR2激动剂的组合,用于将干细胞动员到受试者的血流中。美国专利6,875,753描述了将分子量小于约750,000Da的透明质酸给药于干细胞供体,用于增加供体血液中血液干细胞的浓度。WO 2011/138512描述了至少一种硫酸化的透明质酸低聚物或聚合物与至少一种能够释放干细胞的因子(诸如G-CSF)的组合使用。在美国申请2015/0374736中,尿苷二磷酸葡萄糖用于将来自骨髓的造血干细胞动员到受试者的外周循环中。
然而,目前在现有技术中已知的用于动员造血干细胞的方法的缺点是,干细胞从其在骨髓龛中锚定的释放是不可逆的。这意味着,一旦干细胞进入循环的外周血,它们便无法返回其在骨髓龛中的自然停留处。在施用上述或类似药物后,它们在体内消失。此外,与给药能够动员干细胞的因子(例如G-CSF)有关的不利不良作用如降低的免疫防御/免疫抑制对患者不利,因此应避免。
因此,需要一种新的、改进的方法,其能够使干细胞从它们的起源处动员并在血流中使它们增加,而不会影响干细胞锚定在骨髓龛中的能力。干细胞的可逆脱离将是目前施用的不可逆脱离的优选可替代方案。
在本发明中,令人惊讶地发现,通过施用静脉内激光疗法,干细胞可以从骨髓龛可逆地脱离。以这种方式,干细胞可以非常缓和地释放,并且它们在血流中的数量可以显著增加。
因此,本发明的第一主题是一种将干细胞从骨髓龛可逆地释放到需要这种治疗的患者血流中的方法,包括用激光静脉内照射患者血液的步骤。
干细胞的特征在于它们自我更新和分化成多种专门细胞类型的能力。造血干细胞是多能性(pluripotent)(或多能(multipotent))细胞,具有形成包括髓系和淋巴谱系在内的所有血细胞类型的能力。在本发明中,术语“干细胞”是指任何类型的干细胞。特别地,本发明涉及可以从骨髓龛释放到外周血流中的那些干细胞,例如造血干细胞、间充质干细胞和/或内皮干细胞。在本发明的优选的实施方式中,干细胞是造血干细胞。
造血干细胞目前用于治疗某些血液疾病和非血液疾病。间充质干细胞具有分化成各种细胞谱系的潜力。因此,它们代表了在细胞疗法和组织工程中应用的宝贵资源。间充质干细胞可源自例如骨髓。内皮干细胞是多能干细胞,可以在骨髓中发现。
用激光静脉内照射血液涉及通过将低水平激光送入血管通道而进行的血液体内照明。激光放射到的身体部分可以任意选择。优选地,将激光静脉内放射到例如前臂的静脉中。单色激光通过导管插入静脉中。在20世纪80年代初首次施用静脉内激光血液照射,主要是作为能量增强剂以及能量和活动的健康促进来源。本发明的发明人发现,如果在静脉内施用,则静脉内施用的激光通过增强含有NANA(N-乙酰基神经氨酸)的膜结构的电负性,使在外周血中循环的红细胞在红细胞表面的已经负极化的糖盏(糖杯)带负电。
同时,通过特定的、限定的纳米波长的激光放射,红细胞被触发旋转,这在红细胞的外表面上产生负电场,该负电场对其最接近的周围环境(也对生物分子的电场)具有比已知的范德华力或伦敦力(更强烈)明显更深更强的电负性作用。在从骨髓龛释放干细胞的过程中,所谓的“zeta电位(ζ电位)”对已被激光照射、被电负极化并因此与在不同条件下作为异构体存在的CXCL12-CXCR4轴的二硫桥一起旋转的红细胞的相互作用具有重大影响。静脉内低水平激光增加了具有以H2离子形式的质子供体的所有红细胞致密层内部的剪切平面的zeta电位。这些质子供体-剪切线将能够解开CXCL12之间的二硫桥(也称为SDF-1α),因为在质子供体存在的情况下,二硫桥是相对较弱的结合。
由此,从骨髓龛释放干细胞成为可能。例如,现在有可能释放至少70%或甚至更多的干细胞——其通过二硫桥被正极化并连接,并且其将被红细胞的剪切线触到。
对于根据本发明的静脉内激光血液照射,波长在350-750nm范围内的低水平激光是特别合适的。优选地,用于本发明的激光包括绿光,优选波长在495-570nm范围内,特别是约534nm,和/或蓝光,优选波长在450-495nm范围内,特别是约488nm。在本发明的几个示例性实施方式中,可以使用在400-700nm、350-600nm、500-650nm、500-800nm和/或450-600nm范围内的激光。激光的功率可以例如在1-3nW的范围内,例如约2nW。
通过施用根据本发明的静脉内激光血液照射,干细胞从骨髓龛可逆地释放到患者的血流中。该患者可以是人类或非人类受试者。考虑到出于移植目的从受试者的外周循环收集干细胞的需求,受试者也可能需要这样的治疗,其中移植可以是自体的或同种异体的。在一种非限制性实施方式中,受试者准备捐赠干细胞,特别是造血干细胞。
血流的静脉内激光照射优选在足以用激光影响受试者的大部分血液的时间段内来进行。例如,时间段为至少30min,优选至少40min(对于低水平激光的两种波长,例如488和543nm的情况下)。该时间段足以将大量干细胞从骨髓龛释放到血流中。
在本发明的优选的实施方式中,没有向受试者施用能够同时将干细胞动员到循环血液中的任何细胞因子或其他因子或剂。特别地,优选的是受试者没有接受G-CSF、GM-CSF或CXCR4-受体抑制剂或其任何衍生物、类似物、缀合物或混合物。如国际文献中所述,甲硫氨酸的使用将有助于制备二硫桥区域。
此外,任何透明质酸或其片段或衍生物优选不施用于受试者。如果干细胞从骨髓释放,则它们不得不穿过骨髓和含有透明质酸的骨髓血窦之间的层。经发现,透明质酸或其衍生物的额外给药具有甚至增加该屏障作用的负面作用。
在本发明的一种实施方式中,干细胞向受试者的血流中的释放可用于改变或调节受试者的血细胞的相对量和/或血细胞的类型。
本发明的其他实施方式还包括从血流收获动员的干细胞。因此,本发明提供了一种提供富含干细胞的血样(血液样品)的方法,包括以下步骤(i)用激光静脉内照射受试者的血液,并且
(ii)从受试者取得血样。
通过该方法获得的血样比来自其血液未用激光静脉内照射的患者的血样含有显著更大量的干细胞。由于受试者优选地不接受能够将干细胞动员到循环血液中的任何细胞因子或其他因子和手段,所以血样基本上不含这些物质。就人体中天然存在的细胞因子或物质而言,应理解该定义,因为它们的量没有像如果患者已经外部地被给药这些物质的情况一样增加。
本发明的其他实施方式是来自受试者的血样,其含有增加数量的干细胞。优选地,当与人类受试者的血流中天然循环的干细胞数量相比,该血样中的干细胞数量增加至少20-60%。特别地,外周血中CD34+干细胞的量显著增加。
本发明的血样优选地不含动员干细胞的因子如G-CSF,特别是动员干细胞的外源因子和/或已经被添加到血样所源自的患者中的动员干细胞的因子。这样的因子在上文中描述。
根据本发明优选的实施方式,血样可以用于治疗目的。为此,可以直接使用获得的血样或在使用前处理血样。
此外,可以从血样分离干细胞,然后将其提供用于治疗用途。因此,本发明的另一目的涉及一种从受试者提供干细胞的方法,包括以下步骤
(i)用激光静脉内照射所述受试者的血液,
(ii)从受试者取得血样,以及
(iii)从所述血样分离干细胞。
为了在步骤(iii)中从血样分离干细胞,原则上可以使用任何合适的方法。例如,可以使用的一种方法是单采血液分离术。然后可以将如此获得的细胞培养和/或给药于受体受试者。通常,通过单采血液分离术或其他合适的方法收集干细胞,并作为富集的“单核细胞”部分储存直至使用。
在本发明的优选方面,获得的干细胞可以用于移植。原则上,可以将干细胞给药于获得干细胞的同一受试者(自体移植)或不同受试者(同种异体移植)。优选地,通过注射进行给药。以这种方式,可以将干细胞直接递送至所需的作用部位。在需要系统给药的情况下,干细胞也可以通过输注来给药,从而在血液中运输通过身体。在分离的干细胞优选用于移植的同时,根据本发明也可以使用含有增加数量的干细胞的血样。在这种情况下,血样优选含有比人类受试者的血流中天然循环多至少20-60%的干细胞。
自体移植的优点是在治疗的免疫受损(免疫功能低下)部分期间感染风险较低,因为免疫功能的恢复很快。另外,由于供体和受体是同一个体,所以经历排斥反应的患者的事件非常罕见。
同种异体移植涉及(健康的)供体和受体。与自体移植相比,缺点是供体必须具有与受体匹配的组织(HLA)类型。但是即使是这种情况,也强制性给药免疫抑制药物以减轻移植物抗宿主病。
移植优选自体移植的典型适应症是复壮和组织修复。其他适应症包括淋巴瘤、骨髓瘤和慢性淋巴细胞白血病(chronic lymphonic leukemia)。例如,自体移植适合用化学疗法或放射疗法治疗的患者。在这种情况下,使用本发明的方法将干细胞在受试者中可逆释放并从血流收获。
然后可以用例如大剂量化学疗法和/或放射疗法来治疗该受试者,目的是消灭患者的恶性细胞群,以部分或完全的骨髓消融为代价。然后,患者自己储存的干细胞被输入到他/她的血流中,在血流中它们替换破坏的组织并恢复患者的正常血细胞生成。
当然,自体移植不限于上述用化学疗法或放射疗法治疗患者的情况。也可以从受试者获得干细胞,然后将其局部施用到身体的某些部分,这些干细胞在这些部分可能是有帮助的。例如,干细胞或富含干细胞的血样的移植可用于提供组织修复。而且,它们可以用于复壮的目的。
本发明的另一主题是通过根据本发明的方法获得的干细胞以及包含所述干细胞的药物组合物。优选地,药物组合物不含能够释放或动员干细胞的外源因子,如上文所定义的。
本发明的另一优势是避免了与使用能够动员干细胞的因子有关的不良作用,如贫血或降低的免疫防御/免疫抑制或自身免疫反应,其是典型的,特别是在生长因子治疗的情况下。
药物制剂可另外包含药学上可接受的载体、佐剂、赋形剂、稳定剂、增稠剂或着色剂、粘合剂、填充剂、润滑剂、悬浮剂、抗氧化剂、防腐剂等,或通常在相应产品中发现的组分。根据特别优选的实施方式,药物制剂为液体形式,如注射溶液。
本发明还涉及包含分离的干细胞群的制剂,所述分离的干细胞群源自使用上述方法由哺乳动物受试者产生的收获的干细胞。这些制剂和/或细胞群具有明显的益处,因为它们包含从骨髓龛中起源地可逆释放的干细胞。因此,除非需要这些干细胞,否则它们仍然能够锚定在骨髓中。
Claims (13)
1.一种将干细胞从骨髓龛可逆地释放到需要这种治疗的受试者的血流中的方法,包括用激光静脉内照射所述受试者的血液的步骤。
2.根据权利要求1所述的方法,其中,干细胞选自由造血干细胞(HSC)、间充质干细胞(MSC)、内皮干细胞及其组合组成的组。
3.根据权利要求1或2所述的方法,其中,激光包括波长在350-750nm范围内的光,特别是:绿光,优选波长在495-570nm范围内,例如约543nm;和/或蓝光,优选波长在450-495nm范围内,例如约488nm。
4.根据权利要求1-3中任一项所述的方法,其中,所述受试者将要进行放射疗法或化学疗法。
5.根据权利要求1-4中任一项所述的方法,其中,所述受试者正准备捐赠干细胞。
6.一种从受试者提供血样的方法,其中,所述血样包括增加量的干细胞,所述方法包括以下步骤
(i)用激光静脉内照射所述受试者的血液以及
(ii)从所述受试者取得血样。
7.根据权利要求6所述的方法,其中,所述血样不含能够将干细胞动员到循环血液中的任何因子。
8.一种血样,包括增加量的干细胞,特别是造血干细胞,其中,所述血样不含能够将干细胞动员到循环血液中的任何因子。
9.一种从受试者提供干细胞的方法,包括以下步骤
(i)用激光静脉内照射所述受试者的血液,
(ii)从所述受试者取得血样以及
(iii)从所述血样分离干细胞。
10.根据权利要求9所述的方法,其中,步骤(i)中的照射进行至少30min,优选至少40min。
11.一种将干细胞自体移植到需要这种治疗的患者的方法,包括以下步骤
(i)用激光静脉内照射所述患者的血液,
(ii)从所述患者取得血样
(iii)从所述血样分离干细胞,以及
(iv)将步骤(iii)中获得的所述干细胞给药于所述患者所需的靶位点。
12.干细胞,通过根据权利要求9-10中任一项所述的方法获得的。
13.药物制剂,包括根据权利要求12所述的干细胞。
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