Producer: Popular Science China
Production: Organ reconstruction and manufacturing science team
Producer: Computer Network Information Center, Chinese Academy of Sciences
Competition seems to be the most important theme throughout the evolution of life.
As early as 1859, Darwin published the book "Origin of Species", one of the core ideas of which is "natural selection", which systematically explains that there is competition between biological individuals, and those who can adapt to life will be selected to survive.
Image source: The Paper
There is competition between biological individuals, so is there also competition for the cells, the most basic unit that makes up biological individuals?
If so, what is the cellular competition between different species?
As early as 1974, Spanish scientists first discovered the biological phenomenon of "cell competition" [1].
Scientists have studied Fruit flies as research objects, genetically manipulating a subset of Fruit Fly cells to produce genetic mutations and culture them with normal Fruit Fly cells.
Studies have found that these genetically mutated fruit fly cells die quickly and are replaced by normal fruit fly cells. Another interesting phenomenon is that this cell-to-cell competition can only exist in a culture environment where cells are mixed, and if certain mutant cells make up the tissue, these tissues will not be replaced by normal cells or tissues.
Images courtesy of the author
Today, scientists are using the principle of "cell competition" to try to solve scientific problems that were difficult to make breakthroughs in the past.
Recently, in a new study published online in the journal Nature, researchers found that there is also a certain cellular competition between mouse, rat, macaque, cattle and human stem cells.
By analyzing and regulating key factors that affect stem cell competition between species, the scientists successfully obtained early embryos of human-mouse chimerism.
This achievement may bring new hope to human organ reconstruction.
Image source: Nature's official website
Cellular competition? Artificial organs?
How did it go from universal biological phenomena to human organ culture? Is this omitted too much?
Friends, please don't be impatient, let's talk slowly, this is to start from the embryonic chimeric technique of stem cells.
<h1>Embryonic chimeric technique: Allows human organs to grow in the pig's body</h1>
Stem cells are a special type of cell with high developmental potential, taking embryonic stem cells as an example, they can be isolated from embryos in the early stages of development, with the ability to differentiate into almost all cells, tissues and organs of individuals.
The scientists found that by injecting mouse embryonic stem cells into another recipient blastocyst, the stem cells could grow and develop together with the cells of the inner cell mass of the blastocyst, eventually forming chimeric mice (Chimera) that contain both donor stem cells and recipient embryonic cells.
Embryonic chimerism in mice can be achieved using only the embryonic stem cells of mice, which is even more interesting if there are multiple stem cells of different species.
In 2010, Japanese scientists used stem cells from mice and rats to conduct xenomeric chimeras, in which he injected iPS cells from rats into the blastocysts of mice knocked out by the Pdx1 gene (after which the mice died of pancreatic defects), and successfully obtained pancreatic organs derived from rats in mice, which was the first time that a complete functional organ was obtained in a xenozoan [2].
In subsequent studies, scientists combined stem cells from mice and rats with genetically modified animals to successfully obtain a variety of organs such as thymus and kidneys, and proved that the obtained xeno organs have normal physiological functions.
Using the developmental potential of stem cells, through xenomeric chimerism technology to achieve heterogeneous tissue and organ reconstruction in animals, theoretically can obtain tissues or organs completely derived from human stem cells from non-human species, making stem cell xenogeneous organ reconstruction is expected to become a new source of human transplant organs.
The visualization of xenomorph tissue and organ reconstruction in animals through xenomeric chimerism technique | provided by the author
In recent years, scientists have made certain breakthroughs in the field of heterogeneous chimerism of stem cells.
For example, in 2013, American scientists successfully achieved early human-mouse chimerism by improving the culture system of human embryonic stem cells[3];
In 2017, Chinese scientists improved the chimeric ability of mouse embryos of human embryonic stem cells by improving the anti-apoptotic ability of human embryonic stem cells[4];
In 2019, the chimera of primate monkey-pig also achieved a certain breakthrough [5].
Although many results have been obtained in embryonic chimerism research, the current low chimeration efficiency is an urgent bottleneck problem to be solved in the field of heterogeneous chimerism.
Scientists conclude that the low efficiency of embryonic chimerism may be mainly due to the following reasons: developmental time mismatch, insufficient competitiveness of donor cells, and influenced by evolutionary distance.
Species with large evolutionary distances have large differences in development patterns, difficulty in forming chimeras or low chimeras, and so on.
<h1>Stem cell brawl between species</h1>
On January 28, 2021, Chinese scientist Wu Jun published an article titled "Cell Competition Constitutes a Barrier for Interspecies Chimerism" online in Nature, which revealed for the first time that one of the main causes of chimerism between species is cell competition, and elucidated the mechanisms of cell competition [6].
The scientists first tried pluripotent stem cells from different species such as macro-mouse (rodents), man-monkeys (primates) and cattle for co-culture, and they used the number of cells surviving per square centimeter as an indicator to determine the degree of apoptosis.
Scientists were surprised to find that there is cell competition between different species of pluripotent stem cells.
For example, in the human-mouse pluripotent stem cell culture, on day 3, the human pluripotent stem cells gradually apoptosis, the mouse pluripotent stem cells continue to grow, and on the 5th day of growth, only a few human pluripotent stem cells survive.
Cell co-culture of different species| Image source: Nature
However, what is the difference between these surviving human pluripotent stem cells and individually cultured human pluripotent stem cells?
The scientists also did sequencing analysis, and the sequencing results found that a so-called NF-kappa B signaling pathway in human pluripotent stem cells was activated, indicating that the activation of the above signaling pathway would promote apoptosis.
So scientists have boldly tried, if these genes are regulated in normal cells, will it have an impact on apoptosis?
So scientists inhibit apoptosis by knocking out some key genes in the anti-apoptotic gene Bcl2 or NF-kappa B signaling pathway.
The results were amazing!
Studies have found that genetically modified human pluripotent stem cells can survive in a co-culture environment, and cell competition has disappeared!
In in vivo experiments, after embryo injection, the positive ratio of xenomerism is elevated and donor cells can be found to be involved in embryonic trioderm differentiation.
The genetically modified human stem cell culture process | Image source: Nature
Not only that, the researchers also tried to co-culture stem cells of different species in another state, primed stem cells, comparing the cell competitiveness between them, and the stem cell competitiveness between large mice and human monkeys was similar, and no obvious cell competition was found.
But the status of relative competitiveness between the originating stem cells of large mice (rodents), human monkeys (primates), and cattle is different.
In co-culture systems, this difference in competitiveness states leads to cellular competition, and strong competitiveness induces weakly competitive apoptosis, which researchers believe seems to be closely related to the evolutionary distance between species.
Evolutionary distance and competitiveness status on the evolutionary tree are different| Image source: Nature
If the original cell competition mechanism was like a "black box" in heterogeneous chimerism, then this time the research results are a step to peek into the secret territory of the box.
The study found that cell competition occurs at a specific stage between stem cells of different species, and revealed the mechanism of cell competition, providing a theoretical basis for gaining insight into the barriers that affect the efficiency of heterogeneous chimerism.
When the cellular competition suffered by xeno cells entering the receptor can be effectively controlled by genetic technology, it is believed that xenochimeric chimerism technology will go to another level!
Image credit: veer gallery
The reason why artificial organs and heterogeneous chimerism technology have become the focus of attention is closely related to the current huge gap in organ transplantation, insufficient organ donation, and difficult matching.
There are 300,000 patients waiting for organ transplants every year, but the ratio of organ supply to demand is only 1:30, and only a small number of patients are able to carry out organ transplants.
Artificial organs are one of the most promising ways to solve the problem of organ transplantation gaps, and at present, organ reconstruction has in vitro organ printing, organoids, xenochimerism and other methods.
Cell competition, originally a pervasive biological phenomenon, became the theoretical cornerstone of the possibility of saving tens of thousands of lives before the continuous scientific exploration of truth.
Advances in science have made many myths and stories come true, such as: clairvoyance, the ancient imagination of the downwind ear is a mobile phone and video call, the legend of Chang'e Running Moon reflects the desire for lunar exploration...
Once upon a time, chimera was a monster in Homer's Epic, but in the near future, the development of scientific progress will make chimeras possible to become "mythical beasts" to solve the shortage of human organs, so that more life can get the opportunity to embrace the world again!
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[3] Derivation of novel human ground state naive pluripotent stem cells. [J]. Nature, 2013, 504(7479):282.
[4] Wang X , Li T , Cui T , et al. Human embryonic stem cells contribute to embryonic and extraembryonic lineages in mouse embryos upon inhibition
of apoptosis[J]. Cell Research, 2018, 28(1):126-129.
[5] Fu R , Yu D , Ren J , et al. Domesticated cynomolgus monkey embryonic stem cells allow the generation of neonatal interspecies chimeric pigs[J]. Protn & Cell, 2020, 11(2).
[6] Zheng C , Hu Y , Sakurai M , et al. Cell Competition Constitutes a Barrier for Interspecies Chimerism[J]. Nature, 2021:1-8.