It’s faster, more powerful, and user-friendly. No, I’m not talking about the latest generation tablet, I’m talking about the latest upgrade in stem cell research. The transformation of adult cells from one type to another is common enough. We’ve reported on researchers successfully transforming skin cells into heart, blood, and intestinal cells. This process typically involves converting the adult cell to a pluripotent, stem cell state, from which it can differentiate into one of the specialized forms. As if the cell one day realized that it never really wanted to grow up to be a skin cell, scientists could help revert it back to its infant—or, embryonic—state so it could have another go at life. A recent study by scientists at the Scripps Research Institute in La Jolla, California showcases a different method that bypasses this initial transformation to the stem cell state. Apparently you can teach an old dog new tricks.
Over the last decade scientists have had increasing success in converting skin cells and other types of cells into something different, including heart and blood cells. Efforts are underway across the world to improve the techniques and clinical viability of these cell conversions. The work by Dr. Sheng Ding and his colleagues at Scripps qualifies as a major improvement. The road ahead still requires much work, but it's clear that each day mankind moves closer to producing cells of every type, custom made for your body.
The novelty of the new research coming out of Scripps is not going from skin cells to heart cells beating in a dish—that stuff’s becoming old hat—but that they accomplished it in just 11 days. It is normally a two step process that requires four to five weeks. It also requires a lot more work, owing to the step where the skin cells are converted to induced pluripotent stem cells (iPS). This is done by introducing four genes recently discovered to reprogram differentiated adult cells to embryonic stem cell-like pluripotency. The four genes encode transcription factors, proteins in the cell nucleus that regulate the expression of other genes. Typically the four genes are active for two to four weeks before the differentiated cell is converted to an iPS cell. Ding’s group modified this protocol by allowing the genes to work for as little as four days before deactivating them. The result are skin cells “pushed” in the direction of the induced stem cell state without actually becoming iPS cells. Turns out that’s enough, which, aside from saving time, reveals something new about stem cell biology. The current work was performed using skin cells from mice and it remains to be seen if the shortcut can be applied to human skin cells. Nevertheless, to render the iPS cell stage unnecessary is a major paradigm change for the field and it will be interesting to see if the new paradigm bolsters progress in the near future.
You can see the beating cells in a video below from newsy.com's coverage of the study:
In addition to being faster, Ding’s protocol boosts efficiency. The old protocol yields an estimated maximum of approximately 0.2 heart cells for every skin cell plated. Skipping the iPS cell stage yields a whopping 1.2 heart cells per skin cell. In the paper the team speculates that the increased efficiency is due to the generation of mitotically active cells which are able to divide and multiply. Resembling heart precursor cells, they speculate further that “these intermediate cells, if successfully isolated and stabilized in culture, could become an expandable and renewable source for not just cardiomyocytes, but many other terminally differentiated cardiovascular cells as well.” In the paper they extend this thought, suggesting that the principle of a versatile intermediate might be important, not only for creating the numerous types of cells that go into making a heart, but for stem cell applications in all tissues.
The four genes that researchers use to produce the iPS cells is risky because these same genes can turn cells into tumors. Inactivating them after only a few days instead of a couple weeks reduces this risk. And, like any self-respecting technology, an upgrade is in the making. Because they can turn cells cancerous, stem cell researchers have been searching for a way to reprogram differentiated cells into iPS cells without using the four genes altogether. Demonstrating that the genes are only needed for a few days instead of weeks simplifies the problem and makes the genes easier to replace.
To be sure, stem cell research has a lot of ground to cover before it becomes an effective treatment for disease. For example, the current study was done in mice and it remains to be seen whether or not the shortened protocol produces the same results in human cells. I find it impressive, however, that the four genes widely used by researchers to convert fully-differentiated, adult cells into embryonic-like, pluripotent stem cells were discovered less than five years ago. Since then iPS cells have been gotten by converting other cells besides skin, including cells from the stomach and liver. The current study was the first that we are aware of to bypass the iPS cell stage for differentiation to heart cells, but this shortcut has already been taken for differentiation into blood cells. It is exciting to note that human cells were used in that study.
But in case you hadn’t heard, stem cells have already been used in tissue replacement therapies. We’ve previously reported on tracheal transplants of two women. This involved a donor trachea (from a cadaver) that was coated with a layer of the patients’ stem cells which fostered regrowth of the trachea. Because the new layer of cells originated from the patient the risk of an immune response against the new trachea was minimized.
From my vantage point, it seems that stem cell therapies are inevitable. I also believe that the day is long in coming. Unfortunately it seems that many people have been set up to hope for miracles after the hyperbolic political battles over stem cell research in the past. But therapies rarely come from sudden miracles. Instead it is the incremental advances and shifts in paradigm, such as that achieved by Ding and his colleagues, that will bring us the stem cell therapies we are hoping for.
[image credit: The Scripps Research Institute]