What are induced pluripotent stem cells or IPS cells …

Nobel Laureate Shinya Yamanaka, the first to produce induced pluripotent stem cells.

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, 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 early mammalian development, 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.

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.

Weve been following the IPS cell research field for more than a decade and doing IPS cell research ourselves in the Knoepfler lab. 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, which lights up human IPS cells too.

This post is an overview of IPS cells. It includes recommended resources about them since their first report in 2006 (mouse) and 2007 (human). Also, what are current and future prospects for clinical impact?

While mouse IPS cells were the first reported reprogrammed pluripotent stem cells by Yamanaka, one year later human versions were reported both by the initial discoverer Shinya 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, ranging from adult stem cells to cells that are not stem cells at all such as fibroblasts. In fact, fibroblasts are probably the most common type of cell changed into IPS cells.

How did scientists in the 2000s think that transcription factors might be able to reprogram cells?

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 didnt 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 Hals science well and was a big fan.

When I arrived at the Hutch in Bob Eisenmans lab to start my postdoc in 1998, people were still grieving Hals death 3 years earlier (see his NYT obithere). I also remember the moment I gave the sad news to my doctoral advisor, Mark Kamps, that Hal had passed away. For the first time in my years of working with Mark, he was visibly shaken. He thought the world of Hal and had interacted with him during a long running series of joint meetings between The Hutch and Salk scientists 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.

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 labs seminal work on MyoD, a powerful transcription factor that can induce a muscle cellular phenotype.

Hals labs 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 from1987and1988more 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.

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.

Whats 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.

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.

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 Takahashifor macular degeneration got things going. Now more clinical trials are ongoing.

An articlepublished inNPJ 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 are engaged in clinical work with IPS cells including Cynata and Fate Therapeutics, just to name two.

I predict a few more interventional IPS cell clinical trials are going to pop up soon.

Well continue to see big impact as well from disease modeling and drug screening applications.

A big question is whether for actual interventional trials where IPS cell derivatives are injected into patients, will allogeneic (other peoples cells) or autologous (your cells) will dominate.

In any case, induced pluripotent stem cells have a big future including for personalized medicine.

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