Research in induced pluripotent stem cells (iPSCs) is rapidly moving forward, this being probably the most fast-moving area of stem cell research, a field which itself is proceeding at express speed. I posted a blog entry Rebooting cells and longevity describing iPSCs way back in March of this year (now a time in ancient history) and have referred to them subsequently in various posts. Again, an iPSC is a stem cell that is created by resetting a normal somatic cell, say a skin cell, back to the ground-zero state of an embryonic stem cell by introducing four critical proteins that wipe out the accumulated epigenomic information in that cell. It seems an iPSCs can do most everything an embryonic stem cell (ESC) can do. So, three months later, what are the currently hot issues with respect to iPSCs? Here is what I think they are:
· Creating iPSCs that are genomically stable and free of cancer genes
There is a fair amount of research going on in this area, particularly focused on means for making sure that portions of gene sequences from viral vectors are not integrated into the final iPSCs(ref)(ref)(ref). This is important since such segments might turn out to be oncogenic. The proteins used to create iPSCs can be Oct4, Sox2, Nanog, and Lin28 or Oct4, Sox2, Klf4, and c-Myc. All of these proteins are traditionally known to be oncogenic and that is also a cause for serious concern. If the proteins are activated by inserting genes for them in order to create the iPSCs, it is important to get rid of those genes before the iPSCs are used for therapeutic purposes.
The actions of the proteins can be quite complex, for example see the comments here about the multiple actions of Lin28. This story tells about four current research approaches to getting rid of the cancer genes from iPSCs. Progress in this area is rapid and the expectation is that in a year or two standardized methods will be available for creating iPSCs that are absolutely genomically stable and free of cancer genes. In the meanwhile most experimentation with iPSCs has been with cells that may or may not be safe for human use.
· Determining similarities and differences between embryonic stem cells (ESCs) and iPSCs
This is a very important issue from several viewpoints. A lot more is known about ESCs since they have been studied for several years. If this knowledge can be applied to iPSCs, years of research could be saved. Apart from the religious objections to using fetus-derived ESCs for human therapeutic purposes, there is a compelling reason to use iPSCs instead if they are truly equivalent and safe. The reason is that iPSCs are genetically a patient’s own cells and will not be rejected by the immune system when reintroduced into a patient. Unlike some current stem cell treatments based on using other people’s stem cells, there is no need to wipe out a patient’s immune system before introducing iPSCs. Current research suggests that there may be some differences between ESCs and iPSCs, but exactly what these are and how they play out is still to be explored.
· Getting iPSCs to differentiate reliably into somatic cell types and adult somatic stem cells types
On this front, a recent research report demonstrated that iPSCs can differentiate into functional cardiomyocytes. The author states “We conclude that human iPS cells can differentiate into functional cardiomyocytes, and thus iPS cells are a viable option as an autologous cell source for cardiac repair and a powerful tool for cardiovascular research.” There are a number of earlier reports related to ESCs being able to differentiate into cardiomyocytes. This work on human iPS cells confirms earlier research results with mouse iPS cells(ref). Other reports confirming the pluripotent differentiation capabilities of iPS cells keeps rolling in. For example, scientists at UCLA report creating functional neurons from iPSCs. As time progresses I expect to see reports on more and more tissue types being created from iPSCs.
As for the critical task of regenerating adult stem cells from iPSCs, my cursory scan of the literature has not picked up anything significant yet. It is one thing to get iPSCs to differentiate into neurons; it would be something else to get them to replenish a body’s declining stock of neural stem cells. I believe this is a crucial issue, not only from the viewpoint of designing stem cell therapies but also from the viewpoint of longevity. The fourteenth theory of aging characterized in my treatise on aging is Decline In Adult Stem Cell Differentiation. Having a good available supply of adult (somatic) stem cells is critical for organ damage repair and constant tissue regeneration. Examples mentioned or discussed previously in this blog include mesenchymal stem cells, neural stem cells, endothelial stem cells, dental pulp stem cells, and hematopoietic stem cells. With aging the population of adult stem cells declines due to replicative senescence attrition and oxidative damage, and the rates of differentiation into somatic cells also declines. I would imagine that if iPSCs can be induced to differentiate into nerve or heart cells, they can also be induced to differentiate into the corresponding adult stem cell types which by all logic should be intermediate cell types.
The literature is full of curiosities. For example a very recent study reports that iPSCs created from Tibetian miniature pigs more resemble human iPSCs than those from any other animals. A fascinating related area of research involves direct reprogramming of cell types without intermediation of stem cells. For example, it is possible to transformed human skin cells into mouse muscle cells and vice versa(ref)(ref). The bottom line is far from in yet, and I will continue to watch and report on news related to iPSCs.