Induced pluripotent stem cells or iPS cells just might be the most exciting development in the stem cell field over the last 15 years.
They have unique potential for clinical impact for regenerative medicine too. This may manifest both through their use to produce differentiated cellular therapies and indirectly via disease modeling as well as drug screening.
The scientist who first made them, Dr. Shinya Yamanaka, received the Nobel Prize in 2012 for this discovery. Dr. Yamanaka thought outside the box. He applied basic science knowledge gained over many years about embryonic stem cells and transcription factors.
But the story leading up to iPS cells really starts in the 1980s in part in Seattle. More below.
At The Niche, we do our own IPS cell research
You might have noticed that here on The Niche we have the URL ipscell.com. So when it comes to induced pluripotent stem cells, we know our stuff.
We’ve been doing iPS cell research ourselves in the Knoepfler lab for more than a dozen years. You can see a microscopy image of colonies of human IPS cells that my lab produced years ago. We stained them in red for a human embryonic stem cell marker. This lights up human IPS cells too.
This post is an overview of IPS cells. It includes recommended resources about them. The first reports of iPS cells were in 2006 (mouse) and 2007 (human). Also, what are current and future prospects for clinical impact?
iPS cell discovery
Mouse IPS cells were the first reported reprogrammed pluripotent stem cells by Yamanaka. One year later human versions were reported both by Yamanaka and others including teams led by Jamie Thomson and Rudy Jaenisch.
IPS cells can be made from just about any normal type of cell. The most common source cell type is adult stem cells to cells that are not stem cells at all such as fibroblasts.
How did scientists in the 2000s think that transcription factors might be able to reprogram cells?
Some IPS cell pre-history: MyoD and cell fate
There was a pioneering scientist named Harold (Hal) Weintraub at a place called the Fred Hutchinson Cancer Research Center (or as many of us call it affectionately for short “The Hutch”) in Seattle. You can read more about him here on the Hutch website.
Hal was definitely one of a kind and in a good way. I only met him once when I was a grad student at UCSD and had gone up to the Hutch to give a talk. I didn’t know him, but when I did my postdoc at the Hutch I became very good friends with some of those who had known him well. Without exaggeration I can say they loved the guy and admired his work. I also knew Hal’s science well and was a big fan.
When I arrived at the Hutch in Bob Eisenman’s lab to start my postdoc in 1998, people were still grieving Hal’s death. He died 3 years earlier (see his NYT obit here). I also remember the moment I gave the sad news to my doctoral advisor, Mark Kamps. For the first time in my years of working with Mark, he was visibly shaken. He thought the world of Hal. Mark had interacted with him during a long running series of joint meetings between The Hutch and Salk scientists. These gatherings were called the “Salk-Seattle Meetings”, which sadly no longer take place.
Hal was a visionary researcher in the area of transcription and cellular fate. He might have won the Nobel Prize and deservedly if he had not been taken from us by a brain tumor. At the same time Hal was the kind of scientist and person that I admire.
Why the link between MyoD and reprogramming?
So, you might ask, why do I think Hal deserves some of the credit for the discovery of iPS cells?
He did pioneering studies of how genes influence cell fate. His models of how transcription factors direct cell fate were exemplified by his lab’s seminal work on MyoD, a powerful transcription factor that can induce a muscle cellular phenotype.
Hal’s lab’s first paper (see top portion above) reporting the existence of what would later be called “MyoD” for “MYOblast Determination gene” was truly revolutionary. His team reported the fact that introduction of a single defined factor, MyoD, induced fibroblasts to change into myoblasts that differentiate into myotubes. In fact MyoD sometimes reprogrammed even non-fibroblastic lineage cells into the muscle lineage. (note that a separate, but interesting question is whether some fibroblasts are actually functionally more like stem cells than we might assume).
So in the late 1980s Hal demonstrated a defined factor could induce direct reprogramming of cell fate. This is reminiscent of reprogramming to an IPS cell state.
The Weintraub lab papers from 1987 and 1988 more fully fleshed out the MyoD story.
In a perspectives piece, Yamanaka himself also attributes some of the credit in the pre-history of iPS cells to Hal Weintraub and I admire Yamanaka for that.
What are human induced pluripotent stem cells and how are they made?
The definition of induced pluripotent stem cells is pluripotent stem cells that are made from non-pluripotent stem cells. They behave as though they are embryonic stem cells, but no embryo is needed.
The process by which IPS cells are produced is called “reprogramming”.
What’s that?
It essentially means the starting non-pluripotent stem cells like fibroblasts are recoded gene-expression and epigenetic-wise to “think” they are pluripotent stem cells like embryonic stem cells. Yamanaka used 4 defined factors (OCT4, SOX2, KLF4, and MYC) to complete the reprogramming of human dermal fibroblasts into human IPS cells.
Other groups used similar cocktails sometimes with slightly different combos. The key is that theses factors are fundamental embryonic control switches that tell cells to behave as though they are in the early embryo. You can see a Waddington model of how non-pluripotent stem cells are “pushed” back up the hill to a pluripotent state during reprogramming.
A tricky part of reprogramming is delivering these factors into the starting cells. Most often for research purposes retroviruses are used to transduce the starting cells with the defined factors. For clinical purposes other non-genetic methods are more commonly used such as transient introduction of non-integrating viruses coding the reprogramming factors or introduction of RNAs or the proteins themselves.
How are induced pluripotent stem cells used?
It took a while after their initial report in human form in 2007 to get to clinical trials using differentiated cells made from the IPS cells, but we are now in that exciting phase of this still relatively new field.
You can see my talk at the Future of Genomic Medicine meeting where I give an overview of some of the more exciting applications of IPS cells a few years back. These include actual clinical trials but also disease and developmental modeling. One of the more exciting areas for the latter are human brain organoids made from IPS cells.
IPS cell clinical trials: map, biotechs
In terms of actual clinical trials you can see this overview by my intern Suhas here that also cites some useful papers.
In terms of clinical trials, the pioneering work of Masayo Takahashi for macular degeneration got things going. Now more clinical trials are ongoing.
An article published in NPJ Regenerative Medicine categorizes the PSC clinical trials found on Clinicaltrials.gov. The NPJ Regenerative Medicine report focused on a subset of 131 studies, finding that the majority of them, 77.1%, were observational and did not include the transplantation of any PSC into patients. The remaining 22.9% were interventional.
A search now in 2021 found 129 Clinicaltrials.gov listings related to induced pluripotent stem cells. You can see a clinical trials map above from the database. Note that Japan, while not having that many listings, has a higher % of actual interventional clinical trials.
Several biotech companies do clinical work with IPS cells including Cynata and Fate Therapeutics, just to name two.
Looking to the future
I predict a few more interventional IPS cell clinical trials are going to pop up soon.
We’ll continue to see big impact as well from disease modeling and drug screening applications.
Will interventional trials ever directly inject IPS cells themselves into patients? I doubt it. Will allogeneic (other people’s cells) or autologous (your cells) dominate?
In any case, induced pluripotent stem cells have a big future including for personalized medicine.
References
- Induced Pluripotent Stem Cells: Past, Present, and Future, Shinya Yamanaka, Cell Stem Cell, June 24, 2012.
- Hal Weintraub 20 Years Later, FHCRC Website
- Expression of a single transfected cDNA converts fibroblasts to myoblasts, Robert L. Davis, Harold Weintraub, and Andrew B. Lassar. Cell, December 24, 1987
- Global trends in clinical trials involving pluripotent stem cells: a systematic multi-database analysis, NPJ Regenerative Medicine, 2020.
Vertex and Bayer subs had hesc INDs this month.
Thanks, Brian. I am going to read up on those INDs.
Thank you Paul for this great review of iPSC from many different perspectives. Hal Weintraub and Bob Eisenman were amongst the best professors … I remember well from UW in the 1990s. And Hal’s lab’s myoD work which laid the groundwork for iPSC is not often acknowledged in the general discussions of iPSC so highlighting that research is important.
Further to Don’s point, and as you mention, both allogeneic and autologous iPSC products are being developed for therapeutics, and perhaps a future blog post elaborating the various reasons and considerations for each, as well as hESC compare and contrast, might be good, including how many and which programs are pursuing each… the link to Suhas’ report is also greatly appreciated!
Hi Eugene. That is very cool that you remember Hal and Bob as professors back then. I like the idea of a allo vs. auto kind of blog post. Thanks!
this is a very valuable overview of ips– but i wonder if you could talk a little about the still-unresolved differences between ips and hesc?
Thanks, Don. My sense is that the picture overall is that properly validated IPS cells are functionally the same in almost every case as ES cells. In more subtle ways they are going to be different in some respects such as having epigenetic distinctions. Whether such differences have functional meaning isn’t clear especially clinically speaking. It is also possible in some cases for IPS cells to have picked up a few mutations along the way of their production or that just came along from the person that they were made from, but ES cells pick up mutations too as you grow them.