Un gruppo di ricerca clinica tedesco ha messo a punto una nuova metodica endoscopica per l'applicazione delle cellule epiteliali respiratorie su stent estensibili tubolari
I ricercatori canadesi invitano Governo e partiti a finanziare con 500 milioni di dollari annui per 10 anni il Stem Cell Strategy and Plan
Il Canada apre un “International Hub For Stem Cell Therapy”
Canada's federal government believes that 'regenerative medicine is the future,' and they're ready to put money behind this statement.
Stem cells are remarkable. They have the ability to grow into a plethora of different kinds of cells. As the National Institute of Health notes, they are capable of “dividing essentially without limit to replenish other cells as long as the person or animal is still alive.” And it is precisely this ability to grow and develop into different cell types that makes stem cells so useful in the fight again a host of diseases and ailments.
Now, Canada’s newly appointed Prime Minister, Justin Trudeau, has just announced that the federal government is set to put in $20 million towards the development of the Centre for Commercialization of Regenerative Medicine. The move is set to support the establishment of a stem-cell therapy development facility in Toronto.
“Regenerative medicine is the future and not only is it the future, it’s a branch of medicine that Canada and the province of Ontario are actually quite good at,” said Prime Minister Justin Trudeau. “The medical advances and innovations happening right here in Toronto are world class.”
The stem cell facility has a total cost of $43.8 million, with funding coming both from federal resources and GE Healthcare. However, the government specifies that the money will be provided only once certain terms and conditions are met.
This investment marks the government’s way to support improvement to the new facility and the acquisition of specialized equipment. The Center for Advanced Therapeutic Cell Technologies will also be the first facility in the world to use a collaborative approach between research institutions and industry to solve cell therapy manufacturing challenges.
Many grow hesitant when people start talking about corporations and medical treatments; however, unfortunately, scientists lack the economic resources to be able to make their discoveries widely available to people around the world who may benefit from them. To this end, Canada’s facility is meant to bring scientists together with industrialists to ensure that advancements in stem cell treatments are made widely available.
With the funding in place, The Centre for the Commercialization of Regenerative Medicine is set to become a world leader in stem cell therapy, and it could be life changing for many in need of medical care.
CRISP GENOME EDITING 2015 Breakthrough of the Year
Cheap, widely available, and easy to use, the genome editing system called CRISPR earned Science's 2015 Breakthrough of the Year laurels for many great feats and some controversial ones—including the alteration of DNA in human embryos.
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INTERVISTA AL PROF. YAMANAKA SU JAPAN NEWS 1 GENNAIO 2016
AShinya Yamanaka / Prioritize patients above papers
Regenerative medicine is expected to be one of the ultimate treatments to help patients who suffer from intractable diseases and chronic conditions arising in a progressively aging society. With that in mind, The Japan News conducted an interview with Nobel laureate and Kyoto University Prof. Shinya Yamanaka, a pioneer in iPS cell research, which is a key technology for the development of regenerative medicine in the future.
Q: What do you expect of the future and possibilities of regenerative medicine using stem cells, including iPS cells?
Yamanaka: There are many possibilities in terms of using iPS cells in our medicine. Many patients could be helped by these new strategies. We are now trying to bring iPS cells to patients suffering disease, for example, Parkinson’s disease, Type I diabetes, cancers. I believe that in the next 10 or 20 years, we can come up with many new treatments and therapies by using iPS cells and other related technologies.
Q: Recently, more Japanese researchers have been awarded the Nobel Prize in science. Do you think it is a good sign for the development of Japan’s science and technology?
A: Yes. I am very proud of our country because, at the moment, Japan is No. 2 in terms of the number of Nobel recipients [in the 21st century] in the fields of medicine, chemistry and physics, after the United States. All the Japanese people should be proud of that.
However, at the same time, I need to worry about our future because in most cases the Nobel Prize is awarded for past research results, which were conducted 20 years ago, 30 years ago, even 50 years ago. Many Japanese scientists are actually receiving Nobel Prizes, but that doesn’t necessarily mean we are doing great in science in the present time.
When I was young, in my 30s, I was in the U.S. to do my postgraduate training. I met many young Japanese scientists, doctors and physicians then. But nowadays, I see more and more Asian scientists from China, Thailand, [South] Korea, Singapore, Malaysia, the Philippines, but not many from Japan.
I really hope Japan will continue to keep a leading position in science for a long time. But I’m afraid it may not be the case after five years. We may see more Nobel laureates from countries like China and [South] Korea.
Experience, patient focus drives research
Q: When you were awarded the Nobel Prize in 2012, it was impressive that you said in an interview that failure and discouragement as a surgeon made you stronger as a scientist.
A: That was one factor, that’s for sure. I saw many patients who we couldn’t help at all when I worked as a clinician. Through those experiences, I thought I really wanted to do something to help these patients. The answer was to become a medical scientist. I decided to contribute to medicine and patients in a different way, not as a clinician but as a scientist. I always keep my original vision to perform, to do “science.” It does not mean writing or publishing papers, but helping patients by making new therapies. I think that experience in my early days is very important in my science.
Q: You also said in the interview that you had not been able to get up early due to discouragement after returning from the U.S. How did you overcome such depression?
A: I got depressed to some degree because of differences in the scientific environment and atmosphere between the two countries.
I was already working on mouse embryonic stem cells then. Nobody around us could understand the importance of them.
However, in late 1998, human embryonic stem cells were reported for the first time. That was a big hit to me because we could help thousands of patients by using ES cell-derived brain cells or heart cells. That really activated me again. This is one reason how I overcame scientific depression.
Another reason was that I was lucky enough to be promoted to an associate professor at Nara Institute of Science and Technology in 1999. I got my own laboratory for the first time. The research environment of the institute was very good, like in the U.S. That was the second reason.
Struggle with time, cost
Q: RIKEN’s Masayo Takahashi’s team successfully conducted the world’s first iPS cell (see below) transplantation into retinal tissue. How do you evaluate this trial as a developer of the cells?
A: We helped Dr. Takahashi in evaluating their iPS cells and retinal pigment epithelium cells derived from the iPS cells. We used next-generation sequencing machines to perform whole-genome sequencing of their cells.
Takahashi’s team used iPS cells generated from patients’ own skin cells. That is, it was autologous transplantation.
From that experience, we learned that autologous transplantation is very expensive and also it takes a very long time, at least six months.
I think that, for the next five or 10 years, instead of autologous transplantation, utilizing iPS cells from healthy volunteers is the way to go. Such tissues generated from others are called allografts. By utilizing allografts, the cost can be much lower. We can also prepare cells [for transplantation] in advance.
While there are many advantages of using allografts, the downside of using iPS cells from non-patients is immune rejection.
We need to suppress immune rejection in order to succeed in this method.
The biggest effort to control this problem in this institute [the Center for iPS Cell Research and Application (CiRA), Kyoto University] is to establish a so-called “Stock of iPS Cells” for regenerative medicine. The question is how to overcome immune rejection. We found that, if we make iPS cells from some specific donors — more precisely, donors who have HLA homozygous alleles — we can minimize immune rejection after transplantation.
On the basis of a database of all Japanese HLA types, we have calculated that all we need is 140 lines (donors) in order to cover more than 90 percent of all the Japanese population.
In 2015, we were able to ship the very first iPS cells stock line from this institute. We have distributed that line into institutions. That one line alone can cover up to 20 percent of all the Japanese population. It will be enough to perform clinical studies by using just that one line.
For the future, we would like to go back to autologous cell transplantation. In order to achieve that target, we still need to find a way to generate iPS cells much faster at much lower prices.
That kind of research has been on going in this institute and in other research institutes. As we have seen much progress in that area, hopefully in five or 10 years we can go back to autologous transplantation.
Q: In the U.S., some people including scientists are trying to realize immortality or super-longevity. Do you think these challenges can come true?
A: Cells in a body divide, but there is a limited number of cell divisions. Finally, unless we replace all of our brain cells and all of our heart cells, I don’t think we can live forever. We may perform heart transplantation. However, if we change the brain, I’m not myself anymore. So I don’t think that it will come true.
On the other hand, we are trying to expand our “healthy life expectancy.”
At the moment in Japan, we have the best record of life expectancy. Average women can live up to 86 and men can live up to 80. But healthy life expectancy, which is calculated by the Health Ministry as a measure of the lifetime span in which people can live without trouble, is around 70 in men, and in women must be around 74 or 75. Thus, there is a significant gap between life expectancy and healthy life expectancy.
During the 10 years of that gap, we will be in trouble. So the goal of our research is to shorten that gap.
I really want to live in a healthy way [up to] the time I die. That’s the best scenario of how we die.
Q: Recently, “scientific misconduct” problems have occurred in your field, such as the STAP cell scandal. Why have these scientific misconduct cases never ceased?
A: I believe our area, the stem cell field, is very competitive. As many of our research results can lead to medical applications, many people like venture capitalists, venture companies are paying attention to us. That’s maybe one major reason how this kind of problem happens multiple times in our field.
Traditionally speaking, many results in stem cell fields have been published in leading journals, such as Nature, Science, or Cell. I shouldn’t say “many,” but some of them are very difficult or almost impossible to reproduce.
That kind of history may make it much easier for some bad scientists to fabricate [false results]. Some such scientists may think it will be OK, even if their finding won’t be reproduced by others, because there are many precedent examples in this field. I think that may be another reason.
But after the STAP scandal in 2014, more and more scientists in our field have become very careful. The No. 1 keyword for us is “reproducibility.” Before publishing any important papers, we need to do a double check that other scientists can reproduce our results. It is an important lesson in this field.
Q: How did your father affect you?
A: In many ways. I thank my father.
Actually, he was one of the patients who I could not help. He suffered from liver failure.
Nevertheless, he was very proud of me for becoming a medical doctor.
When I gave him some small medical procedures, such as infusions, despite pain caused by his illness, he seemed to be smiling at receiving some small medical procedures from his own son.
Soon after, he passed away.
After that, I became a scientist.
I often think my father may be upset with my career change.
My father was an engineer, who managed a town parts factory in Higashi-Osaka, Osaka Prefecture. I grew up, in many years, in the house next to his factory. As I watched his work in his factory, I sometimes feel like an engineer myself. It is very important for our work because being an engineer is very application-oriented, not paper-oriented.
Q: How about marathons? Reportedly, you successfully finished running the Osaka Marathon this year.
A: I run three or four times per week. I’m now preparing for the next marathon held in Kyoto in February 2016. Running the marathon means a lot to me.
First of all, I’m running to perform fund-raising. Though we are getting a lot of research support from the government, it is not enough to hire people for a long time. In order to offer them better and more stable employment, I perform fund-raising. Finally, I’m running in order to raise the idea of charity in the minds of Japanese people.
It is also very good for my mental and physical health condition.
Without running, I don’t think I can maintain my mental and physical health because my father and grandfather suffered from Type II diabetes. If I don’t run, I will become very big and suffer from diabetes.
This interview was conducted in English by Japan News Deputy Editor Kyoichi Sasazawa on Dec. 28, 2015.
■ Profile: Shinya Yamanaka
Professor and Director of the Center for iPS Cell Research and Application (CiRA), Kyoto University
Yamanaka was born on Sept. 4, 1962, in Osaka Prefecture. He was educated at the Tennoji Junior High [Middle] School/High School attached to Osaka Kyoiku University. In middle school, he joined the judo team at his father’s recommendation. In 1981 he entered Kobe University School of Medicine. After receiving a medical doctorate from Kobe University in 1987, he earned a PhD from Osaka City University in 1993.
After serving as a professor at Nara Institute of Science and Technology, he was appointed as a professor at Kyoto University in 2004. Yamanaka’s team reported the world’s first generation of mouse iPS cells in 2006 and the generation of human iPS cells in 2007.
Yamanaka shared the Nobel Prize in Physiology or Medicine 2012 with John Gurdon of the United Kingdom. He has also received many prominent awards, including the Albert Lasker Basic Medical Research Award and the Wolf Prize in Medicine.
■ induced pluripotent stem (iPS) cells
These cells have the ability to differentiate into various types of somatic cells. This feature is very similar to embryonic stem (ES) cells, which are controversial because the process of making them involves destroying an embryo. But iPS cells can avoid such a controversial process because the cells are derived from adult somatic cells, including skin cells.
Svelata l'architettura della proteina mTOR
About 25 years ago, Michael Hall discovered the protein "Target of Rapamycin" (TOR) in yeast. It is one of the most studied members of the protein kinase family, an important family of regulatory proteins that control many cellular processes. Later, a TOR kinase was also found in mammalian cells, where it is known as mTOR - the mammalian Target of Rapamycin.
In humans, mTOR is implicated in various diseases including cancer, type 2 diabetes and forms of neurodegeneration. As its name suggests, mTOR is the target of the drug rapamycin. This drug is administered as an immunosuppressant to patients who have received organ transplants in order to prevent their body from rejecting the new organ. Since mTOR is so important for cellular signalling, several mTOR inhibitors have been approved for treatments of diseases such as renal cell carcinoma and pancreatic cancer.
In the mammalian cell, the protein kinase TOR is found in two structurally and functionally distinct protein complexes termed mTORC1 and mTORC2. Both complexes are giant protein structures consisting of mTOR and other accompanying proteins. In these two configurations mTOR carries out various functions such as the control of cell size and growth, as well as the regulation of metabolism and energy balance. However, only mTORC1 is influenced by the drug Rapamycin.
Organisation of mTORC1 elucidated
Due to the great complexity of mTOR complexes it has been very difficult to obtain mechanistic insights into how they work and how they are structured. Previous attempts to uncover the detailed structure of the protein kinase and its partners have been unsuccessful.
However, a collaborative effort between the research teams of Timm Maier and Mike Hall at the Biozentrum in Basel and the group of Nenad Ban at ETH Zurich has now met with success. Interdisciplinary approaches that combined biochemistry, crystallography and electron microscopy were the key to obtaining these exciting insights into the architecture of the protein complex mTORC1. Structure is important for understanding the mechanism of rapamycin action.
"These results, now appearing in Science, are very exciting, because they explain the mechanism of how proteins are recruited to the active site of the complex and how the rapamycin-induced change in the complex composition affects substrate specificity, leading in turn to the pharmaceutical effects of the drug", says Nenad Ban.
The architecture of this huge protein complex is quite exceptional and the results presented reveal the precise interaction sites of the partner proteins and how they are arranged. "Although much is known about mTORC1, our study revealed surprising new insights", adds Maier. Each protein in this complex plays an important role in the regulation of its activity, thereby controlling the intracellular signalling cascade.
Looking at the system as a whole
With their study, the researchers have provided the basis for further investigations that will aim to understand the function of each individual protein in the complex in more detail. "But it doesn't make sense to examine the individual components alone, as the interactions of all the proteins within the complex are critical for its function", explains Maier. "The whole is much more than the sum of its parts."
The finely tuned regulation of TOR activity is very important because even the smallest disturbances can have serious consequences. Thus, dysregulation of TOR signalling pathways plays a role in the development of a number of diseases such as cancer, cardiovascular and neurodegenerative diseases.
Un farmaco usato contro l’osteoporosi protegge dall’invecchiamento
Un farmaco attualmente usato per il trattamento di pazienti con osteoporosi è in grado di proteggere le cellule staminali dall’ invecchiamento, secondo un nuovo studio apparso sulla rivista ‘Stem Cells’.Gli scienziati dell’Università di Sheffield hanno scoperto che il zoledronato è in grado di estendere la durata della vita delle cellule staminali mesenchimali, riducendo il danno al DNA. Il danno al DNA è uno dei più importanti meccanismi di invecchiamento.Il farmaco proteggerebbe le cellule staminali dai danni del DNA migliorando la loro sopravvivenza e il mantenimento della loro funzione di autoriparazione.
“Questo farmaco ha dimostrato di ritardare la mortalità nei pazienti affetti da osteoporosi, ma finora non sapevamo perché”, ha detto la professoressa Ilaria Bellantuono, dell’Università di Sheffield. Circa il 50 per cento degli oltre 75enni hanno globalmente tre o più malattie contemporaneamente, come malattie cardiovascolari, infezioni, debolezza muscolare e osteoporosi.Si spera questo farmaco potrà essere usato per trattare, prevenire o ritardare l’insorgenza di tali malattie.
Researchers mass-producing stem cells to satisfy the demands of regenerative medicine
Growing demand of stem cells in regenerative medicine led scientists to expedite the production of these cells. Researchers at the A*STAR Bioprocessing Technology Institute (BTI) in Singapore have designed a process for mass-production of stem cells. Dr Steve Oh’s group has been growing stem cells by conventional means at BTI for seven long years, when in 2008 his colleague Shaul Reuveny proposed an idea for mass-production.
Stem cells are normally cultured in Petri dishes. Instead of culturing the cells on round, flat Petri dishes, he could try growing them on tiny polystyrene beads known as microcarriers floating in a nutritional brew, suggested by Reuveny, a visiting scientist at BTI now. This technique had been used for decades to mass-produce virus-infected cells for the vaccine industry, which Reuveny had expertise in this area.
The average Petri dish fits fewer than 100,000 cells, a miniscule amount when stacked against the 2 billion muscle cells that make up the heart or the 100 billion red blood cells needed to fill a bag of blood. The approach Reuveny suggested potentially could produce cells in much vaster numbers to make them more practical for therapy.
“Why don’t I bring some of these microcarriers over to you?” Reuveny suggested to Oh. Eventually, Oh was convinced to try what could become the most scalable method for growing stem cells and differentiated cells worldwide.
“There is a trend now in industry to move away from this simple Petri-dish method to manufacturing stem cells in bioreactor processors,” Oh says. “We started this journey much earlier than everyone else in the world.”
Oh’s Stem Cell Group first tried the approach on human embryonic stem cells. These are found in the early embryo and have the potential to mature into any type of cell in the body, a state known as pluripotency. For months, they struggled to develop a coating that would make the stem cells stick to the microcarriers, and to formulate a solution that contained the right mixture of nutrients for the cells to grow. “Without Reuveny’s know-how, we probably would have failed,” says Oh.
About a year into their hard work, one line of human embryonic stem cells survived past the 20-week mark of stability. Not only were these cells viable, they were also two to four times more densely packed than those grown in Normal Petri dishes.
The group has spent the last six years refining their processes to produce even more cells using cheaper materials and fewer steps. “We are easily achieving three times higher cell densities than the Petri dish approach,” says Oh. “In some cases, by modifying the feeding strategy, we can get six times more cell densities, and we could probably reach ten with a bit of work.”
The process can be scaled up exponentially in larger tanks. “If in one week we can go from a ten-milliliter (10mL) culture volume to a hundred-milliliter (100mL) bioreactor, then the next week we can go from a hundred milliliters to one liter; and ten liters the week after that,” explains Oh. The equivalent in Petri dishes from 100 to 1,000 to 10,000 would be practically impossible for a researcher to handle.
The team has also expanded their repertoireto two other types of stem cells induced pluripotent stem cells and adult mesenchymal stem cells as well as differentiated heart, neural, bone and red blood cells.
Therapeutic strategy for hearts
The biggest advances for Oh’s team in recent years have been in the growth of differentiated heart muscle cells, called cardiomyocytes. “We beat the Petri dish method on all counts—purity, yield, cost of goods and simplicity of process,” he maintains.
But a lot of their success is thanks to protocols initially developed on Petri dishes. For a start, cardiomyocytes are the fastest cell type to differentiate, taking only two weeks. And researchers have developed a method to grow pure batches of cardiomyocytes without the addition of expensive growth factors. Instead, they use small molecules to first inhibit and then activate a key cell-differentiation pathway known as Wnt signaling. Oh’s team applied this small-molecule approach to grow and differentiate cardiomyocytes from embryonic stem cells directly on their microcarriers.
The ultimate goal of the research is to grow enough cells in an affordable way to patch up one square-centimeter of damaged heart muscle following a heart attack.
Oh’s team is now partnering with industry to further improve the process, as well as with clinicians to test the healing potential of their cells on animal models. “We always try to keep the end in mind, to translate our work into something that can eventually be used by companies and clinicians.”
Heart cells are just one cell type being grown at BTI. From embryonic stem cells, the team has also developed progenitor cells halfway to becoming mature neurons, as well as dopaminergic neurons that when progressively lost in the brain can cause Parkinson’s disease. And the team is in the early stages of differentiating red blood cells at speeds and scales sufficient for use in emergency blood transfusions.
From mesenchymal cells, for which there are currently more than 400 registered clinical trials worldwide, Oh’s group is growing bone and cartilage cells known as osteoblasts and chondrocytes that can be introduced to animal models to repair damaged tissue.
Preliminary results on the ability of scalably grown stem cells to differentiate into osteoblasts and produce cell-signaling cytokine molecules have been encouraging.
NEW LAW LEGALIZES AUTOLOGOUS STEM CELL THERAPY IN NEVADA
In 2005, I ( Daniel F. Royal, DO, HMD, JD) worked with State Senator Michael Schneider, a member of the Commerce and Labor Committee, to draft legislation that would specifically permit the use of autologous stem cells in the State of Nevada. This legislation eventually became law. It was placed in Chapter 629 of the NRS, which is known as the “Healing Arts Generally,” so that this legislation affects all of Nevada’s state medical boards. Today, Nevada is the only state that has such a law.
In short, Nevada Revised Statutes (“NRS”) 629.300 to 629.390 provide for the banking, administration, compounding, and importation of “nonembryonic stem cells.” Moreover, NRS 629.340 states that “a state professional board, shall not…regulate the activities authorized by NRS 629.300 to 629.390, inclusive; or Take disciplinary action or impose civil or criminal liabilities or penalties against a person for engaging in an activity authorized by NRS 629.300 to 629.390, inclusive.”
In addition, health practitioners also have some federal protection for the use of autologous stem cells. In 21CFR 1271.10, the Food and Drug Administration (“FDA”) states that that stem cells are regulated by the Public Health Services Act, and not the FDA, so long as such cells are not more than “minimally manipulated” and they are “intended for homologous use only.”
Nevertheless, when using autologous cells as a treatment modality in one’s medical practice an informed consent should also be used. Here, the patient will be informed of the procedure itself along with its potential risks. Examples of such risks for using autologous stem cells could include the following:
•pain at blood draw or extraction site;
• light-headedness from blood draw or extraction;
• swelling at intravenous infusion site;
• infection at injection or extraction site (rare); and/or
• “Herxheimer Reaction” (incl. headache, nausea, diarrhea, chills, fever, etc.) from reintroduction of
autologous cells, which is temporary and usually resolves within 24-48 hours.
Although there are ICD-10 codes for the donation (Z52.011) and transplant (Z94.84) of autologous stem cells, as well as CPT Codes for autologous hematopoietic harvesting (38206) and autologous hematopoietic transfer (38215), most insurance companies consider treatment with stem cells to be “experimental.” Consequently, a patient’s insurance is not likely to pay for the procedure. Thus, the patient will also need to be informed they will need to cover the cost of the treatment themselves.
Nevertheless, the use of non-embryonic stem cells is increasingly becoming a primary focus of researchers and clinicians in the stem cell space. This is partly because the use of embryonic stem cells continues to face moral challenges from many governments, doctors, etc. and partly because the use of non-embryonic stem cells has legal support. However, one problem with non-embryonic stem cells has been isolating and expanding their numbers in human tissue. Accordingly, there is a need for developing methods to expand, harvest, reconstitute and reintroduce the non-embryonic stem cells into subjects for use in treating diseases.
All this aside, using pluripotent cells obtained from autologous sources for tissue regeneration is a promising new direction in the search for remission in patients with disease conditions where mechanisms are not always fully understood (e.g., COPD, Parkinson’s, etc.). These pluripotent cells are a potential source for cell replacement as their pluripotency allows them to differentiate into various types of cells that can replace old, damaged, and/or dying cells. When this occurs, it is believed that a disease process may be stopped in its progression and begin to reverse. Therefore, we have a new modality to improve the quality of life for those patients who receive treatment with autologous non-embryonic cells, especially where the development of new disease modifying treatments continues to remain difficult for chronic ailments that are still poorly understood.
Stem cells have two important capabilities: they can develop into a wide range of cell types and simultaneously
renew themselves, creating fresh stem cells. Using a model of the blood forming (hematopoietic) system,
researchers at the Technical University of Munich (TUM) have now been able to precisely determine, which signaling
pathways play an essential role in the self-renewal of blood stem cells. A particularly decisive role in this process is
the interactive communication with surrounding tissue cells in the bone marrow.
Our blood is generated by blood-forming (hematopoietic) stem cells (HSCs) in the bone marrow. In conjunction with
bone marrow tissue cells, these HSCs form a microenvironment known as a niche. As long as the body is healthy,
the HSCs remain in “standby” mode. But if an accident leads to substantial blood loss, for instance, or the defense
against a pathogen requires more blood cells in the course of an infection, the stem cells are activated.
In response, the entire blood cell formation system switches from standby into a state of alert. The activated stem
cells generate new blood cells of every type to counteract the blood loss or combat the pathogen. At the same time,
self-renewal keeps the stem cell pool replenished.
This switch is accompanied by a complex communication process between the stem cells and tissue cells – an area
that had not previously been examined in any depth. “In our study, we set out to establish which tissue signals are
important to stem cell maintenance and functionality, and which HSC signals influence the microenvironment,”
explains Prof. Robert Oostendorp from TUM’s university hospital, Klinikum rechts der Isar, where he works at the
III. Medizinische Klinik led by Prof. Christian Peschel. Together with team members Dr. Rouzanna Istvánffy and Dr.
Baiba Vilne, Oostendorp used mixed cultures of tissue and stem cells to investigate how the two cell types interact.
Tissue cells trigger stem cell renewal
To unravel the complex signaling pathway map, the scientists used their own findings from the analysis of factors
regulated up or down in the interplay between tissue and stem cells, linking them with the signaling pathways
described in existing literature. They then consolidated this information within a bioinformatics computer model. To
achieve this, the researchers collaborated with a group led by Prof. Hans-Werner Mewes, TUM’s Professor of
Genome-Oriented Bioinformatics. Finally, the team conducted extensive cell experiments to confirm the computergenerated
signaling pathway model.
“The outcome was very interesting indeed: the entire system operates in a feedback loop,” reveals Oostendorp.
Summing up the results, he continues: “In alert mode, the stem cells first influence the behavior of the tissue cells
– which, in turn, impact on the stem cells, triggering the self-renewal step.”
Important ramifications also for leukemia treatment
The team’s findings paint a clear picture: in alert mode, the stem cells emit signaling substances, which in turn
induce tissue cells to release the connective tissue growth factor (CTGF) messenger. This is essential to maintain
the stem cells through self-renewal. In the absence of CTGF, the stem cells age and cannot replenish.
“Our findings could prove significant in treating leukemia. In this condition, the stem cells are hyperactive and their
division is unchecked,” describes Oostendorp. “Leukemic blood cells are in a constant state of alert, so we would
expect a similar interplay with the tissue cells.” To date, however, the focus here has been limited to stem cells as
the actual source of the defect. “Given what we know now about feedback loops, it would be important to integrate
the surrounding cells in therapeutic approaches too, since they exert a strong influence on stem cell division,” the
R. Istvánffy, B. Vilne, C. Schreck, F. Ruf, C. Pagel, S. Grziwok, L. Henkel, O. Prazeres da Costa, J. Berndt, V.
Stümpflen, K. S. Götze, M. Schiemann, C. Peschel, H.-W. Mewes, R.A.J. Oostendorp, Stroma-derived connective
tissue growth factor (CTGF) maintains cell cycle progression and repopulation activity of hematopoietic stem cells in
vitro, Stem Cell Reports, October 29, 2015.