Speaker: Hiro Nakauchi
Speaker Institute: Stanford University
Organising Department: Developmental Biology
Subject: From Stem Cells to Organs: Exploiting the organ niche for interspecies organogenesis
Location: Erasmus MC
Author: Nemo Andrea
Hiro Nakauchi is Professor of Genetics Operations at Stanford University. He received his Master’s Degree from Yokohama City University School of Medicine and obtained a PhD in immunology from University of Tokyo Graduate School of Medicine. He did a postdoc at Stanford University. In this seminar, he gave an overview of his research into induced pluripotent stem cells (iPSC) and their applications regarding (interspecies) organogenesis.
His lecture started out focusing on the social relevance of advances in organogenesis technique. It is well known that there is an ever increasing shortage of organ donors. This shortage not only results in many patients being unable to get a transplant they so critically need, but also creates a black market for illegal organ trafficking, resulting in an even greater number of people suffering as a result of organ shortage. He explained how organs grown from the patient’s own cells could resolve these problems. This shows that his research is not just theoretical, but that it is also of great societal relevance.
The discovery of iPSC, as he describes, was a major breakthrough in the field of medicine and biology. It allowed for the generation of stem cells from (theoretically) any somatic cell in the body. While these iPSC can be used in cell therapy to treat specific diseases, they cannot be grown into organs, which are highly complex three dimensional structures. While in theory it should be possible to grow organs fully from iPSC, this is incredibly difficult in practice and may never become a practically attainable option. Hiro and his research group had a solution to this problem that had to be verified experimentally.
The first experiments had as aim to verify the viability of chimeras created by placing iPSC from a donor mouse into a blastocyst of a different mouse. This experiment was successful, as it was found that the resulting mouse was a mosaic of the two cell types. Some cells were from the original mouse and others were of the donor mouse. They decided to take this one step further and one step closer to organogenesis. They made a knockout mouse blastocyst that could not grow a kidney, and once again added the iPSC from a different mouse to the developing blastocyst. They found that the resulting mouse was completely healthy and upon closer inspection they found that the entire kidney was made out of the donor mouse’s cells. Other knockout mice were also successfully rescued from their artificially induced deficiencies.
While these experiments were very promising, one could not conclude whether this would also work for iPSC with xenogeneic barrier. This was also researched by Hiro’s research group and they found that in the same experiment as above, but now carried out with mouse and rat cells still produced viable chimeras and organs. They found that the size of the organism and organs were determined by the species of origin of the blastocyst. They were also able to grow mouse islets in a rat and then transplant those cells into a diabetic mouse and thereby make this mouse recover from its diabetic phenotype.
They were also able to create pig chimeras using the same approach. One big barrier remained: the creating of human iPSC. While human iPSC can be generated, the iPSC that can be created resemble a state later in cell differentiation compared to pig and mouse iPSC. This made chimera formation impossible. At the same time, he mentioned how another problem was also something that had to be resolved: the humanisation of the host animal. It would ethically be hard to grow organs in a half human-pig chimera. He expressed how this could be resolved if it were possible to only have the iPSC create the specific organ desired. Further experiments found a way to allow for chimera formation even out of the (more differentiated) human iPSC. They were even able to allow for chimera formation out of progenitor cells (cells that can only become one cell type/group) which meant they could now overcome both the problem of humanisation, as these progenitor cells can only make a small subset of all body cells (e.g. only liver related cells) and the problem of human chimeras.
This brings us to the current state of research. Research into Human-Sheep chimeras is currently underway. Additionally, one of the reasons why Professor Nakauchi was present to give this talk was because he is here to talk with lawmakers and ethics specialists to discuss how the law should reflect the current state and potential of this technology.
 left: diagram of the main concept;  right: Graphical respresentation of the zenogeneic organ generation
I found it very exciting to hear about this research, as it is truly remarkable how well this all works considering the relatively small knowledge we have of exact organ formation and development. I think there is a lot of room for further research in the exact mechanisms governing this transspecies organogenesis. I intend to do part of my Honours Programme on the topic of iPSC, so this topic is of great interest to me. I hope this research will also be able to eventually result in something that can save the many patients waiting for a suitable donor.