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人工培育肌肉组织获重大进展

更新时间:2014-4-24 14:45:51 来源:华尔街日报中文网 作者:佚名

Scientists Progress In Quest To Grow Muscle Tissue
人工培育肌肉组织获重大进展

Duke University researchers and other scientists are making strides in growing muscle in the lab that not only repairs itself but exhibits strength similar to that of normal muscle.

Using lab-grown muscle could one day help people with certain muscle injuries, including accident victims with big gashes that lead to significant scar tissue. Engineering muscle that works like natural tissue could also accelerate the testing of new drugs: Scientists could use this tissue in place of animals.

Scientists have succeeded in developing ears, windpipes and livers, among other body parts, and even implanted some into humans. Muscle is among the more challenging because the fibers need to have the right structure and fit densely together. It must also be able to contract and exert force like natural muscle. And it needs good blood supply to cells, which can be difficult because muscle is very dense.

Skeletal muscle, the most abundant tissue in the body, typically is very good at repairing itself because it contains many adult stem cells that can create new muscle fibers. With diseases like muscular dystrophy or injuries that cause scar tissue, muscle stops being able to regenerate, which can lead to difficulty moving or even paralysis. Scar tissue, made of collagen, doesn't generate force and thus weakens the muscle. During normal aging, muscles also become weaker and gradually cease being able to repair themselves.

'The hurdle is if there is an injury to try to get new muscle tissue that can form quicker' than scar tissue, says Herman Vandenburgh, a pioneer in the field and a professor emeritus of pathology and laboratory medicine at Brown University.

For about two decades, scientists have been trying to grow muscle in the lab that exerts force and repairs itself, in hopes of one day helping to restore functioning in patients. Understanding the process of muscle regeneration may lead to better understanding of the muscle-wasting process that occurs with aging or disease.

Researchers approach muscle regeneration in different ways, with some growing tissue in the lab that is then used to repair injuries. Others focus on finding genes or a drug that could reverse muscle wasting across the body.

To develop functional muscle, both the structure of the muscle tissue and how it's connected to the blood supply and nerves in the spinal cord are critical. Muscle tissue is dense and made of large muscle cells aligned in the same direction. Without the correct alignment and density, muscle cells can't generate the force they need to power a limb, for instance.

'If you're off with [the structure], then you'll be off with function,' says Nenad Bursac, a professor of biomedical engineering at Duke University.

Dr. Bursac and his team, including first author Mark Juhas, a graduate student, demonstrated for the first time in animals that they could use stem cells to create muscle tissue that repaired itself and grew stronger.

The team published the results in late March in the Proceedings of the National Academy of Sciences.

They also used a new technique for watching the tissue grow by creating a 'window' in the backs of mice that allowed them to see into the animals without harming them and watch the muscle cells regenerate before their eyes.

First, they took muscle tissue from rats and isolated the stem cells, which are the cells that grow into muscle tissue throughout life. Then, after growing more stem cells, they were mixed with a substance containing fibrinogen naturally found in blood clots to help the cells bind together. The combination was placed in a cylindrical mold so that the cells formed long, cylindrical tissue, mimicking the shape of natural muscle.

The scientists tested the tissue in two ways: In a dish, researchers stressed the tissue by applying a toxin to it that destroyed a number of muscle fibers, and then watched to see if the fibers regrew.

The fibers did regenerate. Within 10 days after injury, the muscle regained 80% to 90% of its strength. In a separate experiment, scientists implanted the tissue into a mouse that had a 9-millimeter-wide portal implanted in its back. Within two weeks that tissue increased its strength threefold, into the range of normal muscle strength, Dr. Bursac says.

The group also replicated the work using human muscle stem cells in a dish, though that work hasn't yet been published, according to Dr. Bursac. The researchers are now working on optimizing the growth of human muscle tissue, including finding a way to get blood flow to the tissue, the best source of cells and the best growing medium for the cells.

Other scientists, such as Brown's Dr. Vandenburgh, working with David Mooney's team at Harvard University, have made significant strides using a different stem-cell approach, focusing on implanting human stem cells using the right concoction of biological chemicals to stimulate growth.

Taking biopsies from adult volunteers, including the muscle cells of individuals with congestive heart failure and the frail elderly, and implanting those stem cells into mice, they have been able to demonstrate that they can grow muscle tissue that generates about 90% to 95% of the force of a normally functioning muscle fiber.

Dr. Vandenburgh estimates that the technique could be ready for human clinical trial testing within four to five years. The approach will be best for someone with a specific weakened muscle rather than someone with a disease that causes general muscle wasting, he says.

Early trials could target drooping eyelids, for example, by injecting the stem cells into the muscle around the eye. The hope would be for the healthy stem cells to migrate to the wounded tissue and regenerate it.

Another challenge to using regenerated muscle for therapeutic purposes is the size of the tissue that can be regenerated, experts say. For instance, the mouse calf muscle generated by the team currently is about 20 millimeters long and 4 to 5 millimeters wide, a fraction of the human calf muscle.

Because muscle tissue is very dense, it's difficult to get enough oxygen and blood flow to the muscle on the inside of the tissue, Dr. Bursac says. He and other researchers, such as those at Washington University in St. Louis, are trying to create channels in muscle tissue that can deliver the nutrients the muscle needs.

If they solve this issue, doctors would be able to grow denser and stronger lab-generated muscle tissue. Resolving the issue of how to vascularize muscle tissue will open doors for the treatment potential of regenerated muscle tissue, Dr. Bursac says.

杜克大学(Duke University)的研究人员和其他科学家在利用实验室培育肌肉方面取得了很大的进展。这些肌肉不仅自我修复,还展现出与正常肌肉相近的力量。

有朝一日,利用从实验室培育的肌肉可能能够帮到有某些肌肉创伤的人,比如因为大伤口而长出明显瘢痕组织的事故受害者。制造出像天然肌肉一样发挥作用的肌肉,还有可能加快新药的测试,因为科学家可以用这类组织来替代动物。

科学家已经成功地培育了耳朵、气管、肝脏等人体器官,甚至把一些器官移植到人类身上。培育肌肉的挑战更大,因为肌肉纤维必须拥有合适的结构,从而能够紧密地结合在一起。它还要能够像天然肌肉一样收缩、发力,其细胞需要拥有充足的血液供应,而由于肌肉非常紧密,这一点有时候很难实现。

人体最丰富的组织骨骼肌往往非常善于自我修复,因为它含有很多成年干细胞,可以生成新的肌肉纤维。如果有肌肉萎缩等疾病或形成瘢痕组织的伤口,肌肉就不再能够再生,有可能导致行动困难,甚至是瘫痪。由胶原质组成的瘢痕组织不产生力量,因此对肌肉起到削弱作用。在正常衰老过程中,肌肉也会变得越来越弱,并逐渐失去自我修复的能力。

这个领域内的先驱、布朗大学(Brown University)病理学与检验医学荣誉教授赫尔曼·范登伯格(Herman Vandenburgh)说:“障碍在于有没有一个创伤去努力获得能够比瘢痕组织更快形成的新肌肉组织。”

大约20年以来,科学家一直试图在实验室里培育能够使力并自愈的肌肉,希望有朝一日帮助恢复病人的机能。明白了肌肉再生的过程,或许就能更好地理解伴随衰老或疾病而发生的肌肉萎缩。

研究人员用不同的方法来实现肌肉再生。一些人是在实验室培育肌肉组织,然后用这些组织来修复伤口,另一些人则是侧重于寻找有望逆转全身肌肉萎缩过程的基因或药物。

为了培育拥有机能的肌肉,肌肉组织的结构以及它与血液供应和脊髓神经的连接方式都是至关重要的。肌肉组织很紧密,由同向排列的大型肌肉细胞组成。如果排列方式和密度不合适,肌肉细胞就无法产生移动肢体等所需要的力量。

杜克大学生物医学工程学教授内纳德·布尔萨奇(Nenad Bursac)说:“没有结构,就没有功能。”

布尔萨奇和包括第一作者、研究生马克·尤哈斯(Mark Juhas)在内的团队第一次在动物身上证明,他们可以利用干细胞生成自我修复并逐渐变强的肌肉组织。

3月下旬,团队将实验结果发表在《美国国家科学院院刊》(Proceedings of the National Academy of Sciences)上。

他们还利用一种新技术来观察组织的生长,具体办法是在老鼠背部打开一个“窗口”,从而能够在不伤害动物的情况下察看其内部,看着肌肉细胞在眼前再生。

首先,他们从老鼠身上取下肌肉组织,将干细胞(在生命周期中长成肌肉组织的细胞)分离出来。在培育出更多干细胞之后,就把这些细胞跟一种包含纤维蛋白原的物质混合在一起。(纤维蛋白原天然地存在于血液凝块中,有助于细胞组合在一起)。然后将混合物放进一个圆柱形模具里,让细胞形成长长的圆柱形组织,模仿天然肌肉的形状。

科学家用两种方法测试培育出来的组织。研究人员在一个培养皿里给肌肉组织施放一种毒质,破坏掉一定数量的肌肉纤维,然后看纤维会不会重新生长。

纤维真的再生了。在受伤之后10天内,肌肉恢复了80%到90%的力量。在另一项实验中,科学家将组织植入一只之前在背上植入了一个9毫米宽入口的老鼠。布尔萨奇说,两个星期之内,组织力量增加到原来的三倍,达到了正常肌肉力量的范围。

据布尔萨奇说,团队还利用人类肌肉干细胞在一个培养皿中重复了上述实验,不过实验结果还没有发表。研究人员目前正在着手完善人类肌肉组织的培养,比如想办法让血液流入组织,找到最好的细胞源,以及为细胞寻找最好的生长介质等。

布朗大学的范登伯格博士等一些科学家则利用不同的干细胞处理方法取得了明显的进展。他们侧重于在植入人类干细胞的时候利用适合的生物化学调和物来刺激生长。范登伯格博士跟哈佛大学(Harvard University)戴维·穆尼(David Mooney)团队一起合作。

他们在成年志愿者身上采集活组织标本(包括充血性心力衰竭患者和体弱老年人身上的肌肉细胞),然后把这些干细胞植入老鼠体内,得以证明他们培育出的肌肉组织大约可以达到机能正常肌肉纤维90%到95%的力量。

范登伯格估计,这项技术有望在四五年之内达到做人类临床试验的条件。他说,这一方法将最适合某些肌肉受损的人,而不是身患某种疾病、导致肌肉总体萎缩的人。

早期试验可能会以下垂的眼睑为目标,比如说向眼部周围的肌肉注入干细胞,希望健康干细胞能够进入受损组织,使之重新生长。

专家说,使用再生肌肉用于治疗目的另一重挑战在于能够再生的组织的大小。比如团队目前培育的老鼠腓肠肌约为20毫米长,4到5毫米宽,只占人类腓肠肌的很小一部分。

布尔萨奇说,因为肌肉组织非常紧密,很难让足量的氧和血液流到组织内部的肌肉上去。他和其他研究人员(比如华盛顿大学 路易斯分校(Washington University in St. Louis)的研究人员)正在想办法在肌肉组织中开辟出能够输送肌肉所需营养物质的通道。

如果他们解决了这个问题,医生将能够培育出更加紧密、更有力量的实验室肌肉组织。布尔萨奇说,解决了怎样给肌肉组织建造血管的问题,就会为再生肌肉组织的治疗潜能开闸。

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