Stem Cell Network Blog

Good news for hESC trials: transplanted human embryonic stem cell-derived retinal pigment epithelium… and it’s safe!

2012-01-26T11:37:31-05:00

by Angela C.H. McDonald

As has been reported broadly this week, transplantation of human embryonic stem cell-derived retinal pigment epithelial cells appears to be safe in human patients, and it may even be efficacious (although this can only be confirmed via a Phase II trial).

Advanced Cell Technology (of California) published a preliminary clinical report of their Phase I clinical trials online this Monday in the Lancet. The two Phase I clinical trials were initiated at UCLA’s Jules Stein Eye Institute in July 2011. These trials aimed to treat Stargardt’s Macular Dystrophy and Dry Age-Related Macular Degeneration (two major causes of blindness in the developed world). Each trial will enroll up to 12 patients, with a safety endpoint at 12 months. Four months following transplantation, no adverse affects such as tumorigenicity, ectopic tissue formation, inflammation or cell proliferation could be detected in patients.

The subretinal space of one eye in each patient was injected with retinal pigment epithelial cells generated from human embryonic stem cells. The retinal pigment epithelium is a single cell-thick protective layer in the eye. In the eye of a macular degeneration patient, retinal pigment epithelial cell degeneration causes dysfunction of photoreceptors (which sit on top of the retinal pigment epithelium) and vision in that area of the eye is lost.

Although visual acuity assessments revealed functional improvements in the transplanted eye of each patient, these results should be interpreted with caution. While the Stargardt’s Macular Dystrophy patient only showed improvement in the transplanted eye, the Dry Age-Related Macular Degeneration patient showed improved visual function in both. However, the injected eye did show more improvement than the non-treated eye.

Despite the fact that Monday’s report is very preliminary (results from only two patients at the four-month mark), the company must have a great deal of confidence in the trial for it to have made this public announcement. Additionally, Advanced Cell Technology announced in a press release published on their website Monday that patient enrollment has now begun in the UK for a Phase I clinical trial for Stargardt’s Macular Dystrophy and the first patient was treated in London last Friday.

This exciting news comes just two months after Geron’s announcement to end the first ever FDA-approved human embryonic stem cell Phase I clinical trial, a move described as a strategic financial decision by Geron (covered in a previous blog entry). Disappointment and controversy surrounded the sudden halt of the Geron trial and some question the motive behind this decision. Some speculate that a lack of efficacy in this safety trial is what lead Geron to pull the plug.

Although it felt like the stem cell community took a number of hits in 2011 (including the shut down of the Geron trial and the prohibition of patents for human embryonic stem cell products by the EU), it seems that 2012 is off to a great start.

The “Viagra effect”: how known drugs can be repurposed to target cancer stem cells

2012-01-24T10:43:28-05:00

by Paul Krzyzanowski

Repurposing known drugs for new applications is a strategy with fascinating potential, with two of the most notable examples being Thalidomide and Viagra. Thalidomide was commonly used in the late 1950s as a sedative in pregnant women, later being associated with serious birth defects. Today, it is used to treat multiple myeloma. Viagra was being developed by Pfizer to treat high blood pressure when its ability to ‘treat’ erectile dysfunction was identified as a side-effect, resulting in a complete shift in marketing strategy.

The major allure of finding novel uses for existing drugs is that the long process of early Phase I clinical trials can be sidestepped, as the drugs are already known to be safely delivered. This approach decreases the overall cost of developing drug candidates and brings the development of treatments for rare and neglected diseases closer to reality.

The principle of identifying a drug candidate is straightforward: take a large number of different chemical compounds and test each one for some desired activity. Small molecule screening has long been used by pharmaceutical companies to identify potential drug candidates for probably as many disease conditions as there’s a market for.

Recent years have seen small molecule screening projects being published by academic groups as the required technology becomes more available and public funding is used to promote research with more immediate economic benefits. Some of the most exciting chemical screening studies manage to incorporate knowledge of cancer stem cell biology to yield results that may have immense potential for anti-cancer research.

At The Hospital for Sick Children in Toronto, one such small molecule screening study tested a new kinase inhibitor drug library for agents that inhibit the survival of neuroblastoma cells from patients. Neuroblastoma is one of the most common tumours found in children, with a likely stem cell origin. This work, led by Dr. David Kaplan, was published in Cancer Research and identified several compounds that preferentially inhibit neuroblastoma cell growth.

Kaplan’s team was able to narrow their interest down to BI 2536, a Polo-like kinase 1 (PLK1) inhibitor currently in clinical trials for used against lymphoma and several other adult cancers, and showed that BI 2536 and a new PLK1 inhibitor called BI 6727, significantly reduced neuroblastoma tumour growth in mice. Since their publication, they have repeated their studies using cells from additional patients. As these drugs are already in Phase II trials for other cancers, it seems that they might be brought up to speed for use in pediatric neuroblastoma in the near future. One interesting aspect of Kaplan’s drug screening program is the use of normal pediatric stem cells to ensure that the drugs are not toxic to normal non-cancerous cells.

In another similar study, recent work published in Blood by Dr. John Dick used a 4,000 chemical library to identify kinetin riboside as a compound that kills leukemia initiating stem cells while also preventing their engraftment. By assessing the ability of each compound to inhibit leukemia cell growth, this group was able to quickly narrow 4,000 potential drugs down to 80 (19 of which were already known anti-leukemia drugs).

Using a clever approach to identify the most specific cancer cell killing compounds, John Dick’s team determined the potential toxicity to normal cells for a few dozen of the 80 drugs mentioned above. Kinetin riboside was identified as being three times more toxic to leukemia cells as compared with cells representing the normal hematopoietic system. The results of this study add to other work from the Mayo Clinic showing that kinetin riboside also has anti-myeloma activity by halting the cell cycle, adding bits of evidence that this drug might become a versatile anti-cancer compound in the future.

Unfortunately, kinetin riboside doesn’t seem to be currently in use or in any clinical trials. However, as an aside, the Mayo Clinic’s press release regarding the myeloma study was quick to point out, perhaps a little irresponsibly, that kinetin riboside is found in coconut milk. I don’t know if this press release was the trigger, but there’s a proliferation of web sites touting coconut products as anti-cancer remedies.

For the record, another earlier study did in fact report that kinetin riboside is found in coconut water, but at a very low concentration of under 2 ppb. To provide some context on just how small this amount is, the Ontario limit for lead in drinking water is 10 ppb (for those in the US, the EPA limit is 15 ppb). I want to emphasize that one can’t simply make the leap from carefully controlled studies regarding a potential drug to ingesting it without first showing that it is effective in people and more importantly doesn’t cause any harm. So, while one may decide to drink coconut water, it should not be in place of a proven and possibly life-saving therapy such as chemotherapy.

These insights into new anti-neuroblastoma and anti-leukemia drugs are just two examples of how combining industrial drug screening technology with knowledge of cancer stem cells can yield significant advances in developing new disease treatments. Sometimes the most insightful findings come from work that combines multiple areas of expertise to answer one very incisive question.

Trading on hope: A look at what motivates stem cell tourists and what happens when it goes wrong

2012-01-17T12:11:05-05:00

In recent years, the research community has been quite outspoken in its condemnation of rogue stem cell clinics operating in many countries across the globe. Indeed, through announcements made by health and related ministries in China, India and the US, it appears the message is beginning to be heard.

On the heels of a recent 60 Minutes newscast in the US, a similar exposé aired on January 14 here in Canada. In it, Stem Cell Network Scientific Director Michael Rudnicki spoke with Global TV’s Carolyn Jarvis, condemning stem cell tourism and the agencies that offer them as “despicable” (view the entire Global TV 16x9 segment here). His interview was just a small part of the broadcast, in which the news team looked at the unproven and unapproved therapies offered by a clinic operating in Mexico and a Canadian-based travel operator that offers packages to help people access the services.

Along with Rudnicki, the program profiles several patients, one of whom was successfully treated in an FDA-approved clinical trial for MS, another who was unsuccessfully treated in a Mexican clinic, and a set of parents raising funds to seek treatment in China for their five-year-old son. Each of the struggle to balance the pain of dealing with their ailments, the hope that stem cells could help them, and the risks involved in these experimental therapies.

Exercising caution over unproven therapies: India holds public consultation meetings to update stem cell guidelines

2012-01-12T14:40:35-05:00

by David Kent

Last fall, I wrote on the Eurostemcell documentary film entitled Stem Cell Revolutions: A Vision of the Future, which featured some experimental stem cell treatments in India, and since that time, I have tried to keep my finger on the pulse of what has been happening in India with respect to stem cell therapy.

Last month a pair of interesting statements were made in the India Times:

“As of today there is no approved indication for stem cell therapy as part of routine medical practice, other than bone marrow transplantation.”

This was followed by:

“Hospitals in the city, however, have been making claims of using this therapy to treat several diseases like cancer, leukaemia, spinal cord injuries, cerebral palsy and immune deficiency diseases. Short of alternatives, patients do not mind loosening their purse strings to opt for this expensive therapy if there is hope of recovery.”

While very few would argue that trying out experimental therapies in a controlled manner is unworthy of pursuit, the attachment of high cost to such procedures that are often being borne by local and international patients makes this a wickedly contentious issue. In the face of such controversy and in the wake of bold moves such as the very recent halt that China has put on unapproved stem cell treatments, the Indian government this past month held its fifth and final public consultation on the ethics of stem cell therapy in an effort to update its guidelines to reflect how far its citizens are willing to test things and in what manner the country should move forward. Current guidelines can be found here and it is hoped that these consultations will inform strong evidence-based policy on future stem cell therapies.

However, such evidence does not accumulate on its own, but rather takes a huge amount of effort from trials coordinators, physicians and patients. Together, this underscores the critical importance of running well-controlled and well-regulated trials on stem cell therapies whose results can be shared across the world.

One positive step in the direction of better assessment of current therapies on offer has been from the scientific community. In particular, I am quite pleased that the International Society for Stem Cell Research created the web site A closer look at stem cell treatments in combination with its advocacy efforts for safe stem cell therapies. It shows a deep sense of responsibility and commitment from the expert scientists and clinician/scientists to help people navigate the very murky waters of stem cell therapy. Last year, Irving Weissman spoke about the website’s launch in San Francisco and, amongst many other things, pleaded with scientists to be responsible about which advisory boards they sat on and the ethical approvals that those treatments have put in place.

One thing that I have come to appreciate in my nearly ten years of stem cell biology training is that these cells are extremely potent but still very poorly understood. We have seen evidence of their clinical power in bone marrow transplantations and we are slowly unraveling the inner workings of even more primitive, and more potent, pluripotent stem cells, but we simply do not know that stem cells will behave in the manner we would predict after transplantation into patients. I liken this uncertainty to someone giving a farmer seeds to sow in their field that will give a very high yielding crop, without knowing what it would do to the soil or other plants around it. Would the field be viable in five years? Would other crops be destroyed? Would everything work out just as planned?

With every decision there is a risk and it behooves the scientific and medical communities to be prudent in their approach to stem cell therapy. It is this type of risk assessment that it seems the Indian government is trying to undertake in consultations with its citizenry and its academic and industrial communities. By understanding where people stand on the risks and potential benefits of stem cell therapies and presenting the best evidence possible to help them make that assessment, I suspect that India and other countries doing the same will be in a much better and safer situation in the future.

Sifting through all that monkey business

2012-01-06T09:37:35-05:00

by David Kent

Yesterday, a landmark paper emerged from Cell which reported two major findings to the scientific community:

Primate embryonic stem cells cannot generate chimeras, and
Aggregation and injection of multiple early-stage four-cell primate embryos (not embryonic stem cells) can form chimeras.

Together these findings underscore a fundamental difference between rodent and primate embryonic stem cell lines and show that generating primate chimeras is possible.

As you might expect, this article was heavily publicized (e.g.: The Guardian, The National Post, and the BBC) but it seems that all of the reports focus on the generation of a monkey chimera and not on the more challenging question for scientists that results from not being able to do this from embryonic stem cells. Much of our understanding about embryonic stem cells comes from studies in lower order animal models (frog, mouse, sheep, etc.) and scientists sometimes tacitly assume that this process operates similarly in humans. This not only has major implications for our understanding of early development, but also substantially impacts the struggle to bring stem cell derived therapies and treatments into the clinic.

While it is no doubt an achievement to create primate chimeras, and while it is wonderful that it receives so much attention, I feel that it is exactly this sort of reporting which underpins a very real problem in the relationship between science and the media. Every article I have read gives the sense of “Hooray, scientists have done it again -– look at this great medical advance and imagine the possibilities” rather than “Crisis! Primate embryonic stem cell lines are not like those derived from rodents and challenge our current understanding of embryonic development”. After reading articles with this type of slant, the public, and more worryingly, patients eagerly anticipate more positive news from a set of research findings that are, at best, mixed. Consequently, enormous pressure gets placed on the scientific community to produce more positive headlines.

Indeed, for a more sober reporting of this research paper, one must read the accompanying preview in Cell by Alan Trounson and Uta Greishammer or read the recent review article by Jenny Nichols and Austin Smith, which concludes that human “embryonic” stem cell lines in labs are not as similar to mouse embryonic stem cells as the scientific community would like them to be:

“Although these pluripotent human cell lines are widely used for academic and pharmaceutical research, they tend to be somewhat restricted in their differentiation capacity and are generally more difficult to manipulate than are mouse ES cells.”

Overall, at the risk of sounding like a broken record, stem cell progress, and the progress of the scientific community at large, needs to be viewed with cautious optimism, and therapies from the basic science need to be derived and approved from a substantial evidence base. I fear that unrealistic public expectations and media hype could quickly lead to scientists cutting corners in order to satisfy demand.

Whose life is it anyway? Building patient needs and goals into stem cell clinical trials

2011-12-21T12:01:03-05:00

by Lisa Willemse

In a traditional view of medical research, advances tend to be measured against the overarching goal of cure. Noble as this might be, research is rarely such a black and white affair -- if we have learned anything, it’s that there are innumerable shades of grey.

Even the goal itself can be questioned, especially when achieving it could be 50 years into the future.

Back in 2004, Dr. Kim Anderson published a rather shocking study that revealed a discrepancy between the goals of the spinal cord injury (SCI) population and those of medical researchers. While research had been largely aimed at finding an all-encompassing “cure” for SCI, the patients themselves were more pragmatic, identifying incremental goals focused on partial functional recovery and improved quality of life.

According to the study, recovering the ability to walk is not the first priority of the majority of the SCI population, which lists the top three priorities as hand/arm functionality (for people with tetraplegia), regaining sexual function and recovery of bladder/bowel function.

While many branches of research have been working towards quality of life and functional recovery improvements for people with more chronic SCI, the stem cell field has been largely focused on recent spinal cord injuries with hopes of achieving that overall goal of spinal cord repair or regeneration. Media coverage of the recently-halted Geron trial illustrates just how intense the focus is on stem cells as a potential cure for SCI.

Now there is more to consider. Just last month, another study led by Dr. Brian Kwon was published, which questions whether the SCI population is being left behind in the rush to initiate stem cell clinical trials on patients with recent spinal cord injuries. In the study, the team found that the chronic SCI population (more than 18 months post-injury) demonstrated a much greater awareness of the risks and was averse to undertaking any experimental therapy that might reduce their quality of life. In contrast, the sub-acute (between 1-7 months post-injury) had a greater willingness to consider a clinical trial, despite being less knowledgeable about their condition or about stem cells in general.

As noted by both the researchers and the patients themselves:

“...this is the time when a person with SCI is most vulnerable, poorly informed about the evolution of the condition and options for intervention and is unlikely, therefore, to be able to make an informed decision about participation.”

This is a critical disconnect in research process to the detriment not just of the patient but also of the research community:

“While researchers produce results, and physicians and health care professionals create the bridges between the science and practice, people with SCI must not only seek the fruits of those gains, they must have the opportunity to contribute their experiential, contextualized knowledge to the unfolding story.”

As one participant noted: “Put my voice in there, so it’s actually not just the doctors and physiotherapists doing all the research stuff without having input from the people with the actual spinal cord injuries.”

While the research community takes a collective pause in the aftermath of the Geron trial closure, perhaps this is a suitable time to review shared goals so that, even if we know it’s not all black and white, at least we’re looking at the same shade of grey.

17-year-old high school student makes a cancer stem cell breakthrough

2011-12-14T11:39:47-05:00

When we report on breakthroughs in stem cell research, we typically link to well-funded studies published in peer-reviewed journals by world-renowned scientists. This time, it’s a little different.

Angela Zhang, a high school senior from Cupertino, California, was awarded a $100,000 scholarship for her submission to the 2011 Siemens Competition in Math, Science & Technology: A “gold and iron oxide-based nanoparticle” designed to seek out and destroy tumour-causing cancer stem cells.

In essence, Zhang’s nanoparticle is designed to seek out cancer stem cells in order to deliver salinomycin, a drug that has been found to be very effective at killing breast cancer stem cells in mice, to the cancerous area. Once the particles reach their target, the drug can then be activated with a laser. An added benefit is the inclusion of a gold and iron-oxide base designed to allow for MRI and Photoacoustic imaging, which allows for easier tracking of both the delivery and effect of the drug. The 17-year-old estimates she’s spent about 1,000 hours working on the project.

The Siemens’ competition web site included this comment from one of the judges:

"Angela created a nanoparticle that is like a Swiss army knife of cancer treatment," said competition judge Dr. Tejal Desai, Professor, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco. "She showed great creativity and initiative in designing a nanoparticle system that can be triggered to release drugs at the site of the tumor while also allowing for non-invasive imaging. Her work is an important step in developing new approaches to the therapeutic targeting of tumors via nanotechnology."

The work is still entirely theoretical, but it holds promise as an effective cancer treatment in its ability to target the cancer cells without damaging healthy tissue. There is considerable work (some of which we’ve profiled on this blog) being done in pursuit of more effective cancer treatments, and Zhang’s innovative approach is one of many in the burgeoning area of nanomedicine that may find their way into our medical system in the coming decades.

The apple of a bioengineer’s eye: mature photoreceptors

2011-12-13T10:28:30-05:00

by Angela C.H. McDonald

Last spring, I wrote about the remarkable generation of self-organizing retinal tissue created from mouse embryonic stem cells. The study successfully created all major retinal components including photoreceptors, albeit at a low abundance. However, while multi-layered optic tissue did form, the alignment and organization of mature retinal cell types differed from that of the mouse eye in vivo.

The missing ingredient in this experiment was a physical, instructive cue to direct retinal cells into the complex structural pattern of the eye.

A recent paper published in Biomaterials by another group of researchers described a biomaterials-based approach for creating organized photoreceptor cells from human embryonic stem cells.

Human embryonic stem cells were differentiated into retinal cells and seeded onto a specially designed scaffold positioned on top of a retinal pigment epithelial cell layer. This resulted in the organization of cells into a complex retinal architecture.

The scaffold used in this study was designed with eye development in mind, containing long, narrow, highly packed cylindrical microchannels with spatial dimensions representative of progenitor cell organization in vivo. By mimicking columnar units present in the retina, the stem cell-derived photoreceptors organized into a complex, multi-layered pattern as instructed by the physical constraints imposed by the scaffold.

Retinal maturation characteristics such as the layer separation of photoreceptors and interneurons as well as advanced photoreceptor morphology suggest that these cells may have improved functional properties in vivo, however this was not tested.

While far from the clinic, the correct anatomical orientation of retinal cells directed by this scaffold is exciting.

Many preclinical studies will have to be performed using this system, beginning with transplantation studies in rodent models. Previous transplantation studies of single human pluripotent stem cell-derived retinal cells have shown limited functional improvement but perhaps the transplantation of organized retinal cells in a scaffold will prove to be more fruitful.

While only an in vitro study, these researchers kept clinical translatability in mind and created their scaffold out of an FDA-approved polymer. The polymer called poly (lactic-co-glycolic acid) or PGLA is highly biocompatible and is biodegradable. Within the body, PGLA will degrade into single molecules of glycolic and lactic acid that can subsequently be metabolized by retinal pigment epithelium.

It seems that bioengineers and materials scientists will play an increasingly important role in stem cell therapy efforts by creating tools that provide physical and mechanical cues driving the organization and function of mature cells.

Tick, tock, clock – the clock is ticking for you

2011-12-06T11:41:23-05:00

by David Kent

From the depths of the poetic frivolity of Raphael de la Ghetto come some words that might help guide us through one of the most interesting concepts being pursued by stem cell biologists these days. Specifically, research has emerged which links stem cell behaviour and fate choices to circadian rhythm. The group of Salvador Aznar Benitah in Barcelona recently published research which links skin stem cell turnover and heterogeneity to the body’s internal clock. Their work has inspired many new studies that aim to understand the impacts of circadian rhythm on other stem cell systems.

In tissues that have high turnover (such as the skin, gut, and blood), daily oscillating changes in the balance between making more stem cells (self-renewal) vs. more specialized cells (differentiation) seems a reasonable method for regulating cell number and type. Whether or not these effects are occurring in the stem cells themselves is not fully understood, as stem cells are often regarded as a reservoir of inactive cells that are typically only used when other cell types are in high demand. Furthermore, scientists have known about Clock and Bmal1, two proteins that play a leading role in circadian pacemaking, since 1994 and 2000 respectively, but a strong link to stem cell fate choice had not been made until this paper.

When the ticks turn to tocks

While the Fresh Prince may have had ulterior motives in his recitation, geneticists have made careers from turning ticks into tocks – taking genes away or turning them on inappropriately in order to gain knowledge of genetic functions. The Aznar Benitah study showed that the removal of a major “clock” protein (Bmal1) disturbed the balance of stem cell division and dormancy, which is critical for maintaining the correct balance of stem cells and more mature progenitors. This disturbance in rhythm led to premature ageing as well as an increased incidence of tumours, suggesting that we might better understand how cancers grow and progress by understanding the natural cycles our bodies go through. Aznar Benitah himself discusses this midway through a YouTube clip on his research (start at the 1:56 minute mark for a great description of the research)

Knocking at your door

Where does this leave us? For one thing, this study and others have stimulated a push to understand the relationship of stem cells, transcription, and metabolism, which will undoubtedly lead to interesting discoveries in how our body’s tissues achieve the balance required for lifelong production of the correct numbers and types of specialized cells. However, we should be quite cautious moving forward as this research sits on the interface between the hyped field of stem cell research and a vast catalogue of metabolism altering products (e.g.: pills for weight loss, energy boosting, or anti-aging) and I worry that many a seller of snake oil are laying in the bush, devising ways to take advantage of the links between the two.

Unsolved mysteries in the intestinal crypt

2011-11-29T09:56:22-05:00

by Angela C.H. McDonald

The intestine is an amazing organ. In fact, when I am not reading research related to my thesis, I read about the stem cell population that maintains our gut, the intestinal stem cells (ISCs). And sometimes, the reading reveals most unusual mysteries.

ISCs have their work cut out for them. They must renew the lining of our intestines every few days throughout our lives. ISCs reside in a niche located somewhere within the glands that line our gut tissue (also known as intestinal crypts) however; much speculation and controversy has surrounded the exact identity and location of the ISCs.

Two models of ISCs have been proposed. The first claims that the cells at the +4 crypt position are the ISCs as these +4 cells can give rise to all cells within the mature crypt. The second favours the actively dividing cells at the base of the crypt known as the crypt base columnar cells as these cells can also give rise to all cell types of the mature intestinal crypt.

Back in September a group of researchers reported in Nature that +4 cells are able to repopulate the intestinal epithelium in the absence of crypt base columnar cells. Intriguingly, it was also shown that +4 cells can give rise to crypt base columnar cells, a finding that may suggest that +4 cells are at the top of an ISC hierarchy.

But not so fast – a study published in early November in Science challenges this hypothesis. This team of researchers showed that not only can +4 ISCs give rise to crypt base columnar cells but crypt base columnar cells can also give rise to +4 cells.

Typically, tissue stem cells are less active – or quiescent, dividing infrequently to create one stem cell and one more specialized cell. It was assumed that this predictable behaviour maintains tissue homeostasis within an organ. However, infrequent division does not explain the ability for organs such as the intestine to renew as often as they do.

Researchers previously speculated that quiescent and active stem cells have complementary functions within the tissue, in which the rapidly cycling stem cells would renew tissue while a quiescent stem cell pool would divide on a rare occasion to replace rapidly cycling stem cells.

If this is the case, the question is: why are rapidly cycling crypt base columnar cells capable of giving rise to quiescent +4 cells, especially if that ability is not required as part of normal tissue function? Perhaps this is a stem cell back-up system, another way to ensure long-term maintenance and regenerative capacity of a tissue.

Interestingly, the intestine isn’t the only tissue in which quiescent and fast cycling stem cell populations have been shown to coexist. Similar stem cell behaviour has been observed in the blood and hair follicle systems. In the hair follicle, regeneration is initiated by active hair germ stem cells. These cells arise from quiescent bulge stem cells and are more efficient at responding to regenerative cues; however, they are shorter-lived than bulge stem cells. This suggests that active stem cells initiate regeneration, whereas quiescent stem cells maintain the regenerative capacity of the hair follicle.

While we seem to understand the relationship between quiescent and active stem cells in the hair follicle, as demonstrated by recent publications, we have yet to unravel the exact nature of this relationship in the gut.