中国的两名男子首次接受了由诱导多能干细胞衍生的心肌细胞治疗

2020/7/27 16:35:11 本站原创 佚名 【字体:

two men in China were first to receive heart muscle cells derived from induced pluripotent stem cells

中国的两名男子首次接受了由诱导多能干细胞衍生的心肌细胞治疗

 

廖联明       编译

 

Two men in China were the first people in the world to receive an experimental treatment for heart disease based on ‘reprogrammed’ stem cells, and they have recovered successfully one year later, says the cardiac surgeon who performed the procedures. In May last year, the men were injected with heart muscle cells derived from induced pluripotent stem (iPS) cells, the surgeon told Nature — the first known clinical application of iPS-cell technology for treating damaged hearts.

实施该手术的心脏外科医生说,中国的两名男子是世界上第一个接受基于“重组”干细胞的实验性心脏病治疗的人,并且他们在一年后成功康复。外科医生告诉《自然》杂志说,去年5月,该男性被注射了来自多能干细胞(iPS)细胞衍生的心肌细胞,这是第一个已知的iPS细胞技术用于治疗受损心脏方面的临床应用。

 

No results have yet been published, so researchers not involved in the work have cautioned that there is no way to confirm whether the treatment works, including whether the reported benefits are due to the iPS-derived cells or simply to the heart bypass that accompanied the treatment.

尚未发表任何结果,因此未参与这项研究的研究人员警告说,目前还没有办法确认这种治疗是否有效,包括所报道的益处是否来自于iPS衍生的细胞,还是仅仅是伴随心脏搭桥治疗所致

 

But the surgeon, Wang Dongjin at Nanjing Drum Tower Hospital, spoke to Nature in detail about the procedure and about the patients’ conditions. And one of the men, a 55-year-old electrician who received the treatment alongside a heart bypass — says he is very satisfied with the outcome. Before the surgery, he remembers being tired and often out of breath. Now he can go for walks, climb stairs and sleep through the night. “It was beyond my expectations,” he says.

但是,南京鼓楼医院的外科医生Wang Dongjin向《自然》杂志详细介绍了手术过程和患者的情况。 其中一名男子是一位55岁的电工,他在接受心脏搭桥手术的同时接受了治疗。他说,他对手术结果非常满意。他记得自己在手术之前很累,经常喘不过气来。现在,他可以散步,爬楼梯和整夜睡觉了。他说:“这超出了我的预期。”

 

The team behind the treatment plans to publish the results from the two patients later this year, says Wang Jiaxian, who heads the Nanjing-based biotechnology company HELP Therapeutics that supplied the heart muscle cells, known as cardiomyocytes, used in the study. The group also has approval to expand its study to include a further 20 patients, he says.

南京HELP Therapeutics生物技术公司)的负责人Wang Jiaxian说,该治疗团队计划在今年晚些时候公布这两名患者的治疗效果。该公司提供了研究中使用的心肌细胞。他说,该研究小组还获准将其研究范围扩大到另外20名患者。

 

The trial in China, which is listed on a global clinical trial registry, is not the only one that is ongoing. In January, a cardiac surgeon in Japan, Yoshiki Sawa, introduced iPS-derived cardiomyocytes designed to treat heart disease into a patient — which media reported at the time was a world first. His team is using an alternative approach in which sheets of cells are grafted onto the heart rather than injected into the organ.

在中国进行的这项试验并非唯一正在进行的试验,该试验已被列入全球临床试验注册名单。今年1月,日本心脏外科医生Yoshiki Sawa向患者介绍了旨在治疗心脏病的iPS衍生的心肌细胞,媒体当时报道称这是世界首例。他的团队正在使用另一种方法,即将细胞片移植到心脏上,而不是注射到器官中。

 

Muscle morph

肌肉细胞的形成

 

For decades, researchers have been trying to treat heart disease — a leading cause of death worldwide — using adult stem cells. They hoped that the cells would morph into muscle cells once inserted into the heart.

数十年来,在全球,心脏病是导致死亡的主要原因。研究人员一直在尝试使用成人干细胞治疗心脏病,他们希望这些细胞一旦被植入心脏,就会变成肌肉细胞。

 

But after trials in people proved inconclusive, researchers turned to iPS cells. These are created by inducing adult cells to revert to an embryonic-like state, from which they can develop into other cell types, such as cardiomyocytes. Work with iPS cells is less ethically fraught than that using embryonic stem cells, which can also differentiate into many other cell types.

但在人体试验证明没有结论后,研究人员转向iPS细胞的研究。这些是通过诱导成熟细胞恢复到类似胚胎的状态而产生的,在这种状态它们可以发展为其他类型的细胞,如心肌细胞。与使用胚胎干细胞相比,使用iPS细胞的伦理风险要小一些,因为胚胎干细胞也可以分化成许多其他类型的细胞。

 

Evidence in rodents and monkeys suggests that introducing iPS-cell-derived cardiomyocytes directly into the heart does regenerate muscle tissue and improve the organ’s function. Researchers hope that the first trials in people will reveal the same.

啮齿动物和猴子的证据表明,直接将iPS细胞衍生的心肌细胞植入心脏确实可以再生肌肉组织并改善器官的功能。研究人员希望,在人类身上进行的首次试验也能展示出相同的结果。

 

Wolfram-Hubertus Zimmermann, a pharmacologist at the University Medical Centre Göttingen in Germany, says the first trial in people sounds promising, but because the results have not been published, there is no way to confirm whether the treatment works.

德国哥廷根大学医学中心的药理学家Wolfram-Hubertus Zimmermann表示,首次在人体内进行的试验听起来很有希望,但由于结果尚未公布,因此无法确认该疗法是否有效。

 

As well as the iPS-cell pilot study under way in Japan, several others are planned in France and the United States. Zimmermann is also planning one in Germany.

除了日本正在进行的iPS细胞试点研究外,法国和美国还计划进行其他几项研究。 齐默尔曼(Zimmermann)还计划在德国建立一个这样的研究试验。

 

But researchers are divided over how cardiomyocytes might repair the heart, and whether the best way to introduce them is by direct injection or a graft.

但是研究人员对心肌细胞如何修复心脏以及引入心肌的最佳方式是直接注射还是移植方面存在分歧。

 

We are going to see a lot of interesting shots on goal in the next five years. We don’t know what the answer is going to be. It is time to let the patients teach us,” says Charles Murry, a pathologist at the University of Washington in Seattle who also plans to inject cells into people’s hearts.

“在接下来的五年中,我们将在目标上看到很多有趣的镜头。我们不知道答案是什么。现在是时候让患者教我们了,”西雅图华盛顿大学的病理学家查尔斯·默里(Charles Murry)说,他还计划将细胞注入人的心脏。

 

Safety first

安全第一

 

That there is a trial ongoing in China came as a surprise to many, who didn’t know that researchers there had overcome one of the field’s biggest challenges — the need to produce large numbers of iPS-cell-derived cardiomyocytes that are pure enough to be used in people. This takes a lot of time and effort to get right, so very few companies or research groups have successfully done it, says Murry.

在中国正在进行的一项试验令许多人感到惊讶,他们不知道中国的研究人员已经克服了该领域最大的挑战之一,即需要生产出大量纯度足能够用于人体的iPS细胞衍生的心肌细胞。默里说,这需要花费大量的时间和精力,所以很少有公司或研究团体成功地做到这一点。

 

Wang Jiaxian says that his company has been developing the cells for almost four years.

Wang Jiaxian他的公司开发这类细胞已经将近四年了。

 

Wang Dongjin told Nature that he injected some 100 million cardiomyocytes, derived from iPS cells created using cells donated by a healthy person, around the damaged heart tissue of his two patients. At the same time, both men, who had severe heart disease, underwent a coronary-artery bypass operation, in which vessels from elsewhere in the body are transplanted onto the artery to improve blood flow.

Wang Dongjin告诉《自然》杂志,他在两名患者受损的心脏组织周围注射了大约1亿个心肌细胞,这些心肌细胞来自健康人捐赠的细胞产生的iPS细胞。同时,两名患有严重心脏病的男子都接受了冠状动脉搭桥手术,将身体其他部位的血管移植到动脉上,以改善血流。

 

Wang says his goal was to assess the safety of the cell injections, and that he was encouraged when his patients’ heart function improved significantly after the operation. Neither recipient has developed tumours, he adds, which can be a risk of using pluripotent stem cells.

Wang说,他的目的是评估细胞注射的安全性,当手术后患者的心脏功能显着改善时,他受到鼓舞。他补充说,两名患者都没有出现肿瘤,这可能是使用多能干细胞的风险。

 

To prevent the body from attacking the cardiomyocytes, Wang says, both patients took immunosuppressant drugs. One took them for a month; the other had to stop after a week, owing to side effects. Both men were discharged from hospital less than a month after surgery, he says.

Wang说,为了防止身体攻击心肌细胞(防止产生免疫排斥反应),两个病人都服用了免疫抑制药物。其中一个服用了一个月,另一个则因为副作用一周后不得不停止服用。两位患者都在手术后不到一个月就出院了。

 

Wang also says that the procedure did not cause sustained dysfunction in cardiac rhythm. Zimmermann says that is a sign that it’s safe, although it needs to be trialled in more people to be sure. But the apparent safety of the treatment might also be explained by the low dose of cells the team reportedly used, he says.

Wang还说,该手术并没有引起持续的心律失常。齐默尔曼表示,这是一个安全的信号,尽管它需要在更多人的身上试验才能确定。但他说,治疗的明显安全性也可能是该研究小组所说的使用的细胞剂量低所致。

 

Murry adds that the health benefits the patients have reported cannot be attributed to the reprogrammed cells alone, because the men also received a coronary bypass. “If you do two things to somebody and they get better, you can’t say which one caused it,” he says.

默里补充说,“患者报告的健康益处不能仅归因于重组细胞,因为这些人还接受了冠状动脉搭桥术。如果您对某人做两件事,而他们又变得更好,那么您就无法确定是哪件事造成的。”

 

Best approach

最佳方法

 

Researchers are divided on the best approach to introduce cardiomyocytes into the heart. Injecting them is typically less intrusive than grafting sheets of cells, because it doesn’t require surgery, although the Chinese patients did have surgery for the bypass. Proponents of injections also argue that in animals, the procedure allowed the tissue to better integrate into the heart and produce new muscle3.

研究人员在将心肌细胞引入心脏的最佳方法上存在分歧。注射通常比移植细胞贴片的创伤性要小,因为它不需要手术,尽管中国患者确实进行了搭桥手术。支持注射剂者还认为,在动物体内,这种方法可以使贴片组织更好地融合到心脏中并产生新的肌肉

 

But Philippe Menasché, a cardiac surgeon at the University of Paris, says that the injections puncture the organ in multiple locations, which might damage the tissue. The approach is also not easily reproduced, because the cells are injected somewhat randomly, and sometimes cluster, which could contribute to irregular beating of the heart, he adds.

但是巴黎大学的心脏外科医生菲利普·梅纳塞(PhilippeMenasché)说,注射会在多个部位刺穿器官,这可能会损坏组织。他补充说,这种方法也不容易复制,因为细胞是随机注射的,有时是成簇的,这可能会导致心脏的不规则跳动。

 

Wang says his patients experienced short bouts of irregular heartbeat, but it was not sustained.

Wang说,他的病人出现了短暂的心律不齐,但是没有持续很久。

 

In January, Sawa, a cardiac surgeon at Osaka University in Japan, performed the first in-person trial of the alternative approach: grafting sheets of 100 million cardiac muscle cells derived from a healthy donor onto the diseased tissue of a patient’s heart. Sawa says the patient moved out of intensive care within a few days. He plans to conduct the procedure in eight more people.

今年1月,日本大坂的心脏外科医生Sawa对替代方法进行了首次的人体试验:将来自健康捐赠者的1亿个心肌细胞薄片移植到病人心脏的病变组织上。Sawa说,患者在几天内就搬出了重症监护室。他计划在另外8个人中进行该手术。

 

Work in animals shows that more cells tend to survive being transplanted in sheets or patches than survive being injected.

在动物中进行的研究表明,与注射方式相比,片状或补丁状移植方式的细胞更容易存活。

 

But studies have also found that such grafted cells do not beat in synchrony with the heart. “If you put a patch on the surface, it marches to its own drum. It doesn’t hook up and keep pace with the rest of the heart muscle,” says Murry.

但是研究也发现,这种移植的细胞并不与心脏同步跳动。“如果你移植在表面上,它会自行移动到自己的位置。它不会与其他的心肌相连接,也不会保持同步,”默里说。

 

Researchers are also split on how the sheets work. Animal studies suggest that they might not create new muscle, but secrete growth factors that rejuvenate the existing heart tissue, a process known as the paracrine effect4.

研究人员对移植的片状细胞的工作原理也存在分歧。动物研究表明,它们可能不会产生新的肌肉,而是分泌能够使现有心脏组织恢复活力的生长因子,这一过程被称为旁分泌效应。

 

Menasché plans to test this in people by only introducing the proteins the cells secrete. Zimmermann plans to test whether patches of cells supported by extracellular scaffolding create new muscle cells.

梅纳塞计划仅通过引入细胞分泌的蛋白质来对人进行研究。 齐默尔曼计划研究细胞外支架所支持的细胞贴片是否会产生新的肌肉细胞。

 

Zimmermann thinks that both injections and patches will be useful if they’re shown to work. Injection is more likely to help people who have recently experienced a heart attack and for whom surgery might not be appropriate, whereas patches could be used on those with chronic scarring in tissue where injected cells might not survive. “It will definitely not be case that one of the approaches will be the only one that is going to be useful,” he says. “There is no one size fits all approach.”

齐默尔曼认为,如果证明注射和贴片都有效的话,那么它们都将是有用。 注射更有可能帮助那些最近经历过心脏病发作且可能不适合手术的人,而贴片可用于治疗组织中慢性瘢痕的人,这些组织注射的细胞可能无法存活。 他说:“绝对不会出现其中一种方法将是唯一有用的方法。没有一种方法能适应所有需求。”

 

Nature 581, 249-250 (2020)

doi: 10.1038/d41586-020-01285-w

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