What is the significance of "culturing human pluripotent stem cells from induced somatic cells" to humans?

Recently, the latest achievement of Chinese scientists - "culturing human pluripotent stem cells through inducing somatic cells" was published in Nature. This is a major breakthrough. Although it may not be as sensational as Shinya Yamanaka's, it is a huge progress in the industry (of course, there are still some problems to be solved).

Here is a summary of this research:

1. This study pushed the period of inducing pluripotent stem cells forward by about 3 days, giving induced pluripotent stem cells more differentiation potential.

2. This study innovatively combines single-cell sequencing technology to help find cells with strong differentiation potential, which provides new ideas for our stem cell research.

3. This study still has some shortcomings, and the Nobel Prize is nonsense.

Let me talk about this long article from five aspects.

01. Stem cells and stemness

A human starts from a fertilized egg and eventually develops into a complete individual.

This process is irreversible in the traditional physiological sense.

This process is also accompanied by cell proliferation and differentiation. The former is the process of one becoming many, and the latter is the process of a cell specializing into various types of cells. For example, nerve cells and red blood cells are very different.

According to current knowledge, this is accompanied by a gradual decrease in the stemness of cells. The so-called stemness here can be understood as potential stocks, that is, the stronger the stemness, the more cell types the cell can differentiate into.

Among them, the fertilized egg is the strongest and can directly develop into an individual, which naturally means that it can develop into all types of cells. However, hematopoietic stem cells can only develop into hematopoiesis and cannot develop into nerve cells.

Just like some laymen think that umbilical cord blood is omnipotent, that is nonsense.

So, the question is, how to obtain stem cells from adults?

02. How to obtain human stem cells? ——The origin of induced pluripotent stem cells

As mentioned above, with development, the number of stem cells becomes fewer and their stemness becomes weaker. By the time we reach adulthood, there are basically not many stem cells. Moreover, these stem cells are basically not stem enough and can only differentiate into specific cells (such as hematopoietic stem cells). Other organs may not even have stem cells. For example, the famous myocardial stem cells were later proven to be fake.

But for medical biologists, we really need stem cells. In the short term, it is for scientific research, and in the long term it is for the benefit of mankind. Just think about it, with stem cells, you can get any organ you want, and you don’t have to worry about rejection at all, because that is your own flesh.

Therefore, how to obtain human stem cells has become an urgent issue. How to obtain them?

1. Obtaining it during the early stages of human development is illegal and may even be equivalent to murder, so it is not feasible.

2. We create a new person for it - clone,

But this process is equivalent to starting all over again from scratch. Not only is it not ethically allowed, but in fact, human cloning has not yet been successful, which may be a bit unexpected. Because in science fiction or folk literature, human cloning has long been the exclusive domain of evil people or local tyrants. However, in fact, cloning humans is very difficult. It was not until 2018 that we managed to clone monkeys, let alone humans.

3. Are there other ways to reverse the cells and turn them into stem cells?

This is what the famous Shinya Yamanaka did.

In fact, Shinya Yamanaka was also forced.

When he was working on mice, stem cells came in large quantities. After all, there were as many mice as one could want. But when he started working on humans, he found that he could not find human stem cells. After all, human stem cells are more precious than gold.

There was no other way, so Yamanaka could only solve the problem himself. Finally, he thought of using some ingredients unique to human cells to reverse the cells.

This is the famous Yamanaka Factor. In fact, the process is quite boring, just repeated attempts. Add more water to the noodles, add more noodles to the water, and finally, after repeated attempts, a total of 4 factors are feasible.

Among them are the cancer factor c-myc, transcription factor KLF4 and so on.

This discovery was groundbreaking, so Shinya Yamanaka won the Nobel Prize a few years after he came up with this thing, and almost broke the record for the Nobel Prize in Physiology or Medicine. After all, the verification cycle of this award is very long.

03. Issues with induced pluripotent stem cells

It seems that everything is perfect, and humans can't help but fantasize. But there are still problems in the industry.

1. These factors are risky

Yamanaka factors contain both cancer factors and viral factors. To put it bluntly, this thing can only be used for scientific research, not for practice.

After all, if these factors enter the human body, they can cause cancer if one is not careful, not to mention the viral factors. Therefore, Shinya Yamanaka's research has always remained at the scientific research stage.

So some people wondered if there was a simpler way to do it? A Japanese female scientist started to use her imagination and developed a new induction method, which is to stimulate the cells, for example, eating something sour? After all, sour boys and spicy girls.

She also gave it a good name, "Stimulus-triggered acquisition of pluripotency" (STAP). The whole world was amazed at the time. No one expected that such sophisticated biological science could be so rough.

However, it was eventually confirmed that TM was a fake. So her mentor committed suicide, and she was invited to film. She was Obokata Haruko.

However, the improvement process of others is still ongoing, but they are much more cautious, such as adjusting factors, etc. No matter what, it is just tinkering.

2. This stem cell is not very good

Despite all the praise for induced pluripotent stem cells, there are actually some problems with these cells.

That is: not enough dryness.

The pluripotent stem cells induced by Shinya Yamanaka are equivalent to the state of a fertilized egg at 5-6 days of development. Unlike totipotent stem cells, their developmental potential is relatively limited.

At this time, the cells have actually differentiated to a considerable extent.

To give you an intuitive demonstration, ipsc cannot develop into an individual and cannot grow a placenta in the body.

So, scientists wondered, is there a way to make induced pluripotent stem cells move a little further?

This is the Nature result of our Chinese scientists this time.

04. Stemness-enhanced induced pluripotent stem cells

The Nature article comes from the Chinese Academy of Sciences, Shenzhen BGI Life Sciences and other institutions.

You can simply understand that the stemness period of induced pluripotent stem cells has been pushed forward by 3 days. The induced pluripotent stem cells are equivalent to the embryonic cells of human fertilized eggs at 3 days of development, which is 2-3 days earlier than the stem cells induced by the Nobel Prize before!

Don't underestimate these few short days. During the development period of the fertilized egg, time is calculated by the hours. A difference of a few hours can make a huge difference in the quality of the pregnancy.

Basically, it can develop into most organs.

Because conversely, when doing in vitro fertilization, 8 cells are available.

The reason why stem cell development can be advanced this time is actually due to single-cell technology. What is single-cell sequencing technology? It is quite complicated. Generally speaking, you can understand it as a more detailed decomposition of cells.

For example, people generally believe that humans have only a few dozen types of cells, but in fact, research has found that there may be as many as thousands. For example, even a single heart has dozens of cell types, which is a new classification method.

It is not based on appearance, but on gene expression. However, this technology is still relatively expensive, so BGI can do it, but I can't. I also received a recommendation from a biological company yesterday.

This time they used the DNBelab C4 platform and then used DNBSEQ sequencing technology to sort the cells, so that they could pick out some cells with higher stemness.

The specific process is as follows

Induce the cells first, then start the single-cell sequencing screen.

This is the chromatin map of the selected cells (it is so beautiful, I have started to learn it)

This is the transcriptome profile of 4CL naïve PSC and 8CLC

You must be confused, right? These pictures are for professionals. All you need to know is: we have found a cell with the potential equivalent to a fertilized egg three days old.

05. Is there any problem?

Of course, always remember this sentence: there is no perfect scientific research in this world.

This study also has some problems.

1. Dryness problem

The current speculation on the dryness of this article is too idealistic. In fact, there is currently insufficient evidence to support its dryness.

In other words: many people think that the stem cells found this time are amazing, but in fact, these are just inferences, and the article did not provide any evidence. So, this is a pity.

Of course, if we find more evidence in the future, it might be possible.

2. This article needs more verification

The conditions used this time are different from those in previously published papers, so they cannot be compared with previous studies. This is also the reviewer's opinion, so more research will be needed to verify this.

3. The fundamental problem of induced pluripotent stem cells has not been solved

This article does not solve the natural defects of induced pluripotent stem cells that we mentioned, so it has no application value. However, it can provide a corresponding basis for scientific research.

So, let’s look forward to the future.