引用本文： 康裕建. 再生医学-医疗模式转化的催化剂—2017 年 TEDx 合江亭演讲. 华西医学, 2018, 33(12): 1466-1470. doi: 10.7507/1002-0179.201812066 复制
How many of you are 60 years old and over? Please raise your hands. How many of your parents are over 60 years old? Please raise your hands. Do you know or have you heard what people over 60 years old often talk about? What I often heard is this: “My doctor placed a couple of stents in my hearts” or “My doctor told me I need seven stents in my heart, I just placed a couple and wait for a while to place more”. Then they will talk about saving money for future disease treatment. I call this aging population syndrome, which is saving money for disease. How many people involved in this aging population? According to WHO, between 2000 and 2050, the number of people aged 60 years old and over is expected to increase from 605 million to 2 billion, about 11% to 22% of the world population.
Our life span is elongated, this is a good news. But there are about 80% of the ageing population suffer from serious illness. Think about this, if I were laid on bed from age 80 to 90 under daily medical attention, causing serious social and family burdens, what is the point to elongate my life span? Then someone asks me you can now make 3D bio-printed blood vessels, how about print organs for replacement? Yes, the 3D bio-printing technology would allow us to develop such applications. But I would like to tell you that I myself and my team would not make effort to print human organs for transplantation. Organ replacement is a disease-based end stage treatment, which does save life, but does not meet today’s need for improving quality of life. I believe we should transform the disease-based medication to personalized healthcare, focusing on improving the quality of life. I tell you why?
One of my friends recently told me that his doctor told him his coronary arteries already have 30% blocked because of atherosclerosis plaques, but cannot do much except wait for further growth of the plaques to cause life threatening problem, then bypass or vascular stents can be used to reopen the vessel conduit. What he can do now? The only option is to use some Statins drugs to slow, but not to stop, the growth of the plaques. In another word, he waits for his disease to grow to meet the standardized treatment procedure, i.e., standard disease-based medication. By then he would suffer from a long-term reduced blood supply to many organs, and already had many personalized chronic diseases.
My friend asked me: Can doctor just simply stop the growth or remove the plaques from me, so that I will never develop to the end stage disease? I told him not now, but we definitely can do it in the future if we take action now. Our modern age knowledge and big data information generated from clinical practice allow us to create new technology, called Regenerative Medicine.
So what is regenerative medicine? Why do we need it? And how does it work? Regenerative medicine simply is to recover the function of failing organs through integrated approaches involving stem cells and related technologies. Stem cells are naturally occurred in our body and capable of repairing injured tissues. For instance, if you have a finger cut, you may not do anything but it is healed without notice. This is the process of self-repair. In this process, the injured tissue releases injury signals to recruit the repair material to the injury site. The materials to repair the injury are stem cells. Thus, stem cells are naturally existing personalized medication.
Why do we develop chronic disease although we are equipped with personalized medication or stem cells? We can think about this in two ways; the first is that if an organ is constantly insulted and the damage is overwhelming the capacity of stem cells for functional repair, a non-functional repair will take place, such as the formation of scar tissue, which will interfere with normal function leading to chronic disease. The second, in aging population, the self-repair capacity is reduced leading to cumulative organ damage from the same insult that may not cause disease in youth. These two problems are all related to the shortage of stem cells.
Now you may wonder how to make more stem cells available for regenerative medicine? Let’s first examine where stem cells are in our body. We all start from a single fertilized egg cell in our mom’s womb. During the embryonic period, the embryo develops into three layers, the ectoderm, the endoderm, and the mesoderm; and stem cells rapidly divide and differentiate to different organs. Some stem cells are also stored in our organs, such as mesenchymal stem cells in the mesoderm organs and bone marrow stem cells in our bone marrow. These stem cells are mobilized locally and from bone marrow when an organ is injured and needs to be repaired. The stem cell can be removed from our body, expanded outside of our body, and then reintroduced to our body to repair the injured organ.
Now you may ask how do stem cells work in our body? First, stem cells once in our body need to know where to go. On the surface of the stem cells there are detectors that can detect the injury signal, then where the injury signal comes from? Second, once the stem cells arrive in the injured organ, how do they act to repair the injury?
The first, how does an injured organ send signals? When an organ is injured, it will release some cellular molecules or chemicals, attracting stem cells to the injured site for repairing. But if there are not enough stem cells, a scar tissue will be formed to make a non-functional repair. The tissue will no longer send injury signals. If you introduce stem cells into the body, they don’t know where to go. If you simply force stem cells into the injured organ such as through injection, they would not stay in place. Let’s think about the ceramic tiles covered on the floor in your house, what would happen if one of the tiles was damaged, but cannot be replaced because you do not have the replacement tile? You may use cement to cover the empty space, which doesn’t look or feel the same. Now, you get the replacement tile, what you would do is to remove the cement first, and then place the tile in place.
The non-functionally repaired organ was covered by scar tissue, to repair it we need to remove the scar tissue first. This scar tissue removing re-activates the tissue injury signaling, or changes the injury from chronic to acute state, calling for self-repair mechanism to work again. By providing sufficient stem cells through cell expansion from the same patient, the re-repair takes place, leading to organ regeneration.
The second, how do stem cells repair the injured organ? We did an experiment. We removed mesenchymal stem cells from monkey’s own fat tissue. After cell expansion, we packed the cells in a spheroid envelop composed of biodegradable materials; we call it Biosynsphere. We used the biosynspheres as bio-ink and applied the bio-ink to a novel 3D bio-printer to produce a stem cell vascular graft that was covered by a prosthetic vascular graft. The hybrid vascular graft was implanted as an interposition graft to replace a 2-cm-long segment of the abdominal aorta in the monkeys. We observed the changes of the implanted grafts at different times, and found that a complete vessel structure was formed about 4 weeks after the implantation, including endothelium layer, smooth muscle layer, and integrated collagen structure. In this process, anticoagulant heparin was used only in the first 5 days to prevent blood clotting. We made 47 implantations in 34 monkeys, and all of the regenerated vessels have normal function for the longest observation of more than 280 days.
I need to tell you that the mesenchymal stem cells are removed from the monkey’s own body, only 5 gram fat tissue is sufficient for a 2 cm vascular graft. It has no problem at all to remove 5 gram fat from anyone of us, even you are a skim model girl. If you say “I am too old”; no problem, you can ask your son or grandson to donate 5 gram fat for your use. It has been proven it does work well in monkeys.
So what can we conclude? First, injured organ is capable of a self-regeneration as long as there are sufficient repair materials supplied; second, the fat tissue mesenchymal stem cells are good enough and efficient for regeneration of multiple tissues of the blood vessel; and, third, personalized medicine is realized by rejuvenation of the naturally occurred self-repair process. This process isorchestrated by the injured site. We call this “Destination-Engaged Vector Evolving Lineage Organ Regeneration”, or simply called DEVELOR.
Thus, we can use our own stem cells to repair cumulative damages at early stage, preventing the development of the end stage of chronic disease. This will transform our medical practice from disease-based medication to personalized healthcare focusing on improving the quality of life, not simply expanding life span. By 2050, most of you will reach to age 60, I hope when you gather together then, you will talk about something more exciting than saving money for disease.
冯莉 译四川大学华西医院再生医学研究中心（成都 610041）Email: firstname.lastname@example.org
假如我们偶遇年逾古稀长辈们的闲聊，我们大概会听到这些内容：“最近我的心脏刚装了支架”“医生告诉我需要装 7 个支架，我现在只装了 2 个”等等。然后，讨论的话题必然会过渡到如何存钱治病。“存钱治病”本身似乎也已经成为现代老年群体必须面对的一种疾病，我给这种病起了个名字，叫做“人口老龄化综合征”。那么，到底有多少人已经或者即将步入老龄呢？据世界卫生组织数据显示，从 2000 年到 2050 年，全球 60 岁以上人口将从 6 亿 500 万飙升至 20 亿，更可怕的是，其在全球总人口中的比例将从 11% 上升到 22%。
人均期望寿命的不断延长绝对是件好事。可我们也应当看到，近 80% 的老龄人口不得不承受各种严重疾病带来的痛苦和困扰。试想，如果我们整天躺在病床上，依靠各种药物度过从 80 岁到 90 岁的每个日夜，还必须时刻担心高额的医疗费用。这样的“高寿”，又有什么意义呢？
接下来你一定会问我这样的问题：既然 3D 生物打印血管已经成为现实，那么是否可以使用该技术打印人体器官，通过移植取代受损脏器，从而延长我们的生命呢？当然，3D 生物打印技术绝对可以让这种梦想成为现实。但我要告诉大家，我和我的团队不会将人体器官打印作为我们的目标。因为，器官移植只是针对疾病终末期的一种传统治疗方式，这种方式确实能够挽救生命，但它仍然不能满足当代人们对提高生命质量的需求。我坚信，聚焦于人类生命质量的提高，将传统的“以病为本”的医疗模式向“以人为本”的个性化健康干预模式转变，才是医学发展的正确方向。
接下来你肯定会问，那要怎样才能获取足够多的干细胞以用于再生医学？首先我们需要确定干细胞在体内所处的位置。我们的人生旅程都开始于母亲子宫里的一个受精卵细胞。在胚胎阶段，胚胎发育为 3 个胚层：外胚层、内胚层和中胚层。期间，干细胞快速分裂并分化形成不同的器官。其中一部分干细胞会在出生后一直储存在我们的器官里，如中胚层器官中的间充质干细胞、骨髓中包含的骨髓干细胞。与之相应，当器官受损需要修复时，干细胞有两种来源：一是器官自身含有的干细胞，它们立刻可以原位修复；二是骨髓来源干细胞，从骨髓迁移至受损器官进行修复。这是人体内的自然修复方式，而医学上运用干细胞进行人为治疗的常用方式是将干细胞从体内取出，在体外培养扩增甚至修饰，然后被重新输入体内去修复受损器官。
第二个问题，干细胞如何修复受损器官？在一项实验中，我们从恒河猴自体脂肪组织中提取了间充质干细胞。在细胞扩增之后，将这些干细胞封装在一层生物可降解材料制作的球状包裹中，我们称之为“生物砖”。这些“生物砖”作为墨汁被 3D 打印机打印成类似血管的管腔状结构，其外层用人工血管包覆。然后，我们通过外科手术将 2 cm 打印的人工血管替换恒河猴的一段腹主动脉。通过不同时间点观察植入血管的变化，我们发现在手术 4 周后，人工血管内就产生了完整的血管结构，包括内皮层、平滑肌层及胶原支持结构。在整个过程中，只需在前 5 天对恒河猴使用抗凝剂-肝素以防止凝血。截至目前，在 34 只恒河猴，47 次手术，最长达 280 多天的观察过程中，所有移植的人工血管都在其体内发挥着正常功能。
我想告诉大家，实验所用的间充质干细胞均从恒河猴自身提取。仅 5 g 脂肪组织就足够制作出 2 cm 人工血管。提取 5 g 脂肪对任何一个人来说都不是问题，哪怕你是一名骨感超模。如果你认为自己年纪太大，不适合提取干细胞。请放心，可以请你的儿女或者孙辈捐献 5 g 脂肪。猴子实验已经证明这同样具备可操作性。
综上所述，第一，只要提供充足的再生材料，受损组织就能够进行自我再生。其次，脂肪间充质干细胞完全可以满足血管中多种组织的再生需要。第三，个性化医疗通过再次激活个体自主修复系统实现，这个过程由受损部位调控。我把这套理论体系称为“Destination-Engaged Vector Evolving Lineage Organ Regeneration”，简称为 DEVELOR。
因此，我们能够利用自身干细胞在疾病早期对累积损伤进行修复，防止病症发展为慢性疾病终末期。这将有助于“以病为本”的传统医疗模式向聚焦于提高生命质量，而不仅是延长寿命的“以人为本”的健康模式转变。到 2050 年，当在座的大多数都已年逾古稀时，我希望大家再次相聚时，会聊一些比存钱治病更有趣的事情。