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Concise Review: Adult Multipotent Stromal Cells and Cancer: Risk or Benefit?

Concise Review: Adult Multipotent Stromal Cells and Cancer: Risk or Benefit?

Gwendal Lazenneca,b, Christian Jorgensena,b

 

ABSTRACT

This review focuses on the interaction between multipotent stromal cells (MSCs) and carcinoma and the possible use of MSCs in cell-based anticancer therapies. MSCs are present in multiple tissues and are defined as cells displaying the ability to differentiate in multiple lineages, including chondrocytes, osteoblasts, and adipocytes. Recent evidence also suggests that they could play a role in the progression of carcinogenesis and that MSCs could migrate toward primary tumors and metastatic sites. It is possible that MSCs could also be involved in the early stages of carcinogenesis through spontaneous transformation. In addition, it is thought that MSCs can modulate tumor growth and metastasis, although this issue remains controversial and not well understood. The immunosuppressive properties and proangiogenic properties of MSCs account, at least in part, for their effects on cancer development. On the other hand, cancer cells also have the ability to enhance MSC migration. This complex dialog between MSCs and cancer cells is certainly critical for the outcome of tumor development. Interestingly, several studies have shown that MSCs engineered to express antitumor factors could be an innovative choice as a cell-mediated gene therapy to counteract tumor growth. More evidence will be needed to understand how MSCs positively or negatively modulate carcinogenesis and to evaluate the safety of MSC use in cell-mediated gene strategies.

 

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Activation of Wnt Signaling in Hematopoietic Regeneration

Activation of Wnt Signaling in Hematopoietic Regeneration

 

Kendra L. Congdon, Carlijn Voermans, Emily C. Ferguson, Leah N. DiMascio, Mweia Uqoezwa, Chen Zhao, Tannishtha Reya, Ph.D. *

 

ABSTRACT

Hematopoietic stem cells (HSCs) respond to injury by rapidly proliferating and regenerating the hematopoietic system. Little is known about the intracellular programs that are activated within HSCs during this regenerative process and how this response may be influenced by alterations in signals from the injured microenvironment. Here we have examined the regenerating microenvironment and find that following injury it has an enhanced ability to support HSCs. During this regenerative phase, both hematopoietic and stromal cell elements within the bone marrow microenvironment show increased expression of Wnt10b, which can function to enhance growth of hematopoietic precursors. In addition, regenerating HSCs show increased activation of Wnt signaling, suggesting that microenvironmental changes in Wnt expression after injury may be integrated with the responses of the hematopoietic progenitors. Cumulatively, our data reveal that growth signals in the hematopoietic system are re-activated during injury, and provide novel insight into the influence of the microenvironment during regeneration.

 

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Nuclear Magnetic Resonance Metabolomic Footprinting of Human Hepatic Stem Cells and Hepatoblasts Cul

Nuclear Magnetic Resonance Metabolomic Footprinting of Human Hepatic Stem Cells and Hepatoblasts Cultured in Hyaluronan-Matrix Hydrogels

William S. Turnera,b,c,d, Chris Seagleb, Joseph A. Galankod, Oleg Favorovb, Glenn D. Prestwiche, Jeffrey M. Macdonaldb, Lola M. Reida,b,c,d

 

ABSTRACT

Human hepatoblasts (hHBs) and human hepatic stem cells (hHpSCs) were maintained in serum-free Kubota's medium, a defined medium tailored for hepatic progenitors, and on culture plastic versus hyaluronan hydrogels mixed with specific combinations of extracellular matrix components (e.g., type I collagen and laminin). Nuclear magnetic resonance spectroscopy was used to define metabolomic profiles for each substratum tested. The hHpSCs on culture plastic survived throughout the culture study, whereas hHBs on plastic died within 7–10 days. Both survived and expanded in all hydrogel-matrix combinations tested for more than 4 weeks. Profiles of hundreds of metabolites were narrowed to a detailed analysis of eight, such as glucose, lactate, and glutamine, shown to be significant components of cellular pathways, including the Krebs and urea cycles. The metabolomic profiles indicated that hHpSCs on plastic remained as stem cells expressing low levels of albumin but no alpha-fetoprotein (AFP); those in hydrogels were primarily hHBs, expressing AFP, albumin, and urea. Both hHpSCs and hHBs used energy provided by anaerobic metabolism. Variations in hyaluronan-matrix chemistry resulted in distinct profiles correlating with growth or with differentiative responses. Metabolomic footprinting offers noninvasive and nondestructive assessment of physiological states of stem/progenitor cells ex vivo.


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Testes Yields Versatile Stem Cells - Jan 09

STEM CELLS

Volume 27 Issue 1, Pages 138 - 149

Published Online: 5 Jan 2009

Nina Kossack 1 2, Juanito Meneses 3, Shai Shefi 4 5, Ha Nam Nguyen 1, Shawn Chavez 1, Cory Nicholas 1, Joerg Gromoll 2, Paul J. Turek 4 *, Renee A. Reijo-Pera 1 *||
1Institute for Stem Cell Biology and Regenerative Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Palo Alto, California, USA
2Center of Reproductive Medicine and Andrology, University of Muenster, Muenster, Germany
3Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California, USA
4Department of Urology, University of California, San Francisco, San Francisco, California, USA
5Sheba Medical Center, Tel Hashomer, Israel

 

News Items:

San Francisco Chronicle Jan 13 2009          Testes found to yield versatile stem cells

STEM CELLS Journal Names Co-Editors

DURHAM, N.C., Nov. 15 /PRNewswire/ -- AlphaMed Press, publisher of the journal STEM CELLS(R), has named Donald G. Phinney and Miodrag Stojkovic as co-editors.

Curt I. Civin, current STEM CELLS Editor, retires after eight years of unprecedented growth in areas of the journal's most significant metrics: Impact Factor, number of pages published, and number of manuscripts submitted. During his tenure as editor-in-chief, Dr. Civin was assisted by three outgoing senior editors: Alan M. Gewirtz, Robert G. Hawley, and Margaret A. Goodell.

Successful Cloning of Human Embryo

DURHAM, N.C., January 17 - A California research team has become the first to report, and painstakingly document, the cloning of a human embryo using donated oocytes (egg cells) and DNA from the cells of an adult donor. The study was published online today by the journal "Stem Cells."

Mouse Adult Stem Cells Developed into Heart and Blood Cells

DURHAM, N.C., April 30 - Researchers have succeeded in inducing stem cells grown from mouse skin cells to differentiate into functioning cardiovascular and blood cells, according to a study publishing online tomorrow in the journal "Stem Cells."

"Induced Pluripotent stem (iPS) cells are reprogrammed cells obtained by genetic manipulation of normal adult cells that then express capabilities similar to embryonic stem cells," explains Dr. Miodrag Stojković, Co-Editor of "Stem Cells." "That is, iPS cells are theoretically able to differentiate into 220 different cell types. For the first time, scientists from UCLA were able to induce the Differentiation of mouse iPS cells into functional heart cells, smooth muscle cells, and blood cells."

3rd Annual Young Investigator Award Presented at International Stem Cell Symposium

Durham, NC & Seoul, Korea, June 20, 2008 – The journal STEM CELLS® announces that Lena Motoda, MD, PhD won the 3rd Annual STEM CELLS® Young InvestigatorAward.

additional excerpts - James Thomson

 

Additional excerpts from our interview with Dr. Thomson


Stem Cells Portal (SCP):

Work in the field of human embryonic stem cells involves the use of surplus and donated human embryos. This has always been a somewhat controversial issue in the public realm, and thus this research has always had to undergo evaluation, regulation, and even approval by people who are not scientists.

How did this affect your work in 1998?

 

James Thomson (JT):

Prior to that it wasn't clear how this would be perceived in the public realm, so before initiating the work I talked with some very good ethicists on campus, discussing the implications. The work has been heavily scrutinized from the beginning, which on the whole is a positive thing.

However, the controversy has somewhat hindered the field because it has led to financial implications. NIH grants would not fund this at the beginning, and now only on a limited number of cell lines, which may have limited the number of people entering the field.

SCP:
What was the reaction of the public vs. the scientific community to your derivation of the first hESC lines?

 

JT:
The scientific community was generally positive. The public in Madison was positive, it's a very liberal place, but there were of course differences of opinion elsewhere.

SCP:
As somebody who stands on the frontier of hESC research today, how do you think this will affect the future of hESC research?

 

JT:
I think most of the controversy has gone away already with the exception of the current administration; both new candidates for president have indicated their support for this research. One thing that President Bush did do was let this research go forward, even in a restricted way, which has at least opened the door to this field, and that door cannot now be closed. Also, this was not as damaging to the basic research at the time. The existing cell lines were OK for this at the time, however as time has gone on that policy has become more damaging.

 

SCP:
Please comment about your feelings as to the importance of public discussions and lectures regarding ESC research.

 

JT:
I have done a lot of this over the years, mostly early on, not as much now due to time pressures. What I've learned is that the press is a medium that informs the public but does not educate them. In the first 6 months of the Bush presidency it was clearly a hot topic news story, with new stories every day, but in polls it seemed that the public still really had no idea what these cells were or where they came from. I don't know how to change that. The science reporters who get the initial story usually do a very good job, but there is still a problem getting it out to the public. With public lectures, it really only gets out to a small audience
.

 

SCP:
Please comment on the problems you feel are associated with:

a) suboptimal in vitro growth conditions

 

JT:
This isn't such a problem anymore, they grow well, the medium has improved a lot over the last 10 years.

 

SCP:
b) genetic manipulation of hESCs

 

JT:
They are actually as efficient as mouse cells as things like homologous recombination, just their doubling time is different, so experiments in humans take longer.

SCP:
c) our understanding of epigenetic mechanisms and targeted differentiation of hESCs

 

JT:
It's almost certain that there are epigenetic changes, the question is, how significant are these changes? There are many labs looking into this, but how critically important these mechanisms are is not clear yet. The genetic changes probably are a big deal when considering transplants (re: changes in genes over time in tissue culture). Making sure these transplants are safe will probably take years to work out.

SCP:
Do you believe that ultimately iPS cells will be most useful as a model to study human disease, or are they likely to provide patient-specific cell therapies?

 

JT:
They will likely be most useful as model systems. Immunorejection was never the major limiting factor that has kept stem cells from being used in therapies. It's getting them to functionally integrate in a way that repairs the tissues But the ability to control genetic background should help our ability to research drug development.

 

SCP:
The development of new technologies and the protection of these technologies is am important topic for consideration. Unfortunately, we have as yet no world-wide policy or strategy regarding the patenting of hESC work.

What direction do you think scientists and policy makers should be taking on this issue?

 

JT:
I really don't know. It seems that the original reason for patents in Britain was that they allowed information to get into the public domain, in return for a limited amount of time to develop it, which I think is a very good use for patents. But in academics that model doesn't make sense because you are already motivated to get things out into the public domain. So it really hinges on whether having these patents facilitates commercialization of the product, which is a good thing, but it's hard to say how much it really benefits us since we don't have a parallel universe where these things don't exist.

 

SCP:
What are some of the biggest challenges you faced as a student and new investigator, and what strategies did you use to meet these challenges?

 

JT:
I took such a back door approach, it was unusual. I found a way to keep myself employable without having to live from RO1 to RO1 like most people do. The work with primates was also very difficult to get funding for. So always look at alternatives that aren't in the normal track, because the percentage of PhDs who get jobs in academics these days is pretty low.

SCP:
What advice would you give to young scientists in the field today who are trying to balance the demands of work and family/personal life i
n this increasingly demanding and competitive field?

 

JT:
I don't have great advice for this because I got married very late! I now protect my time with my family in a way that if I was just starting out I really couldn't because the demands in the lab are so high. That's a very difficult issue.

 

SCP:
What do you feel is one of the most important experiences or defining moments in your education, career, or life that has contributed to your success as a researcher?

 

JT:
I think everyone has some sort of a mentor, teacher, etc. that has at some point inspired them in some way. For me it was a biologist when I was an undergraduate. I don't know why this guy had such an influence on my, but I changed from a mainly math and physics major to biology because of him. It takes a unique individual who is there at the right time and actually cares about you as an individual.

additional excerpts - Rudolf Jaenisch

Additional excerpts from our interview with Dr. Jaenisch

 

Stem Cells Portal (SCP):

Work in the field of hESCs involves the use of surplus and donated human embryos.  This has always been a somewhat controversial issue in the public realm, and thus this research has always had to undergo evaluation, regulation, and even approval by people who are not scientists.  How has this affected your work?

Rudolf Jaenisch (RJ):

Well the work with mESCs has of course been untouched by this controversy.  For hESCs, it has affected me because work with non-presidential human ES cells is cumbersome in this country.  If you want to work on your own non-presidential hESC lines, you have to go through the hassles of separating your laboratory and this work from all of the other federally funded research in this area in your lab and your institute.  And it is difficult to raise money or to write a grant for this work, so these are all hurdles, which I think are substantial.

SCP:
As somebody who stands on the frontier of hESC research today, how do you think this will affect the future of hESC research?

RJ:
I think it will be less and less.  The policy in this country (USA) has been so extreme that it only can become better with whoever forms the next administration here.  There are certainly other countries, like Germany, that are extreme, and they are facing even worse problems than we in the US.

SCP:
There are many confusing data that Oct4 has been detected in adult stem cells and tissues. In your opinion, how important is Oct 4 for somatic cell self renewal?

RJ:
I think it was very attractive to think that Oct4, being the key gene that is important for self renewal of ESCs, might also have a role in adult stem cells.  Indeed, there were hundreds of papers that said they found Oct4 expression in adult stem cells, in the gut, blood, skin, etc., but not in the progenitor cells, which are not immortal.  The evidence was either staining for protein, or PCR.  When I looked at most of those data I was really worried, because the controls were not good and the PCR seems to have been really stretched to its limit, and was unconvincing.  So we looked at this very carefully in mice.  We took a mouse and deleted the Oct4 gene in the adult tissues, and asked if it made any difference to the tissue homeostasis in various tissues.  And there was absolutely no difference – we found that the tissue didn’t need Oct4 in the adults.  And then we stressed these mice.  For instance, we irradiated them, to slough off the intestinal epithelium and found that the mice without Oct4 could regenerate their intestinal epithelium as well as the controls. The same results with the blood and the skin – there was no difference in regeneration even when you stressed the system – the Oct4 deficient stem cells renewed the tissues.  Then we asked the question, could we see Oct4 expression in these cells.  By staining we couldn’t see it.  But by PCR, we detected a low signal (10,000 times less than ESC cells).  However, the signal was there regardless of whether or not the gene was there!  We saw the same signal in mice in which we had deleted the gene as in mice which had the gene.  So obviously this was at the limit of PCR detection and the signal was an artifact.  So basically from our studies, and I stress they were in mice, there is no functional role of Oct4.  Hopefully this will put to rest some of this controversy. 

There is also another interesting argument for this.  We also know that Oct4 is a powerful oncogene. If you express Oct4 ectopically in the mouse, they immediately develop tumors. It’s as powerful an oncogene as c-myc.  So if Oct4 was expressed normally as part of the normal adult stem cell renewal, it should show up as an oncogene all over the place, in many tumors, but it never does.  What that says to me is that this gene is so well silenced that it doesn’t get activated, and has no role in adult development.  Putting this together makes me very much doubt the evidence from people who claim it has some role in normal adult stem cells.  This does not mean that in tissue culture cells, under certain circumstances, this gene could not get reactivated.

SCP:
We know many things about the epigenetic background and profile of animal embryos, but not human embryos. There are some studies which claim that intracytoplasmic sperm injection (ICSI) and assisted reproduction can result in humans in Beckwith-Wiedemann (B-W) syndrome. Do you believe it is assisted reproduction itself, or some specific part of these medical treatments, for instance, suboptimal in vitro culture conditions, that is causing this condition?

RJ:
There are several studies indicating that the incidence of B-W does go up several fold, but the number of patients with B-W is still very low.  I think it is a very interesting finding and a concern.  We know from mouse that when you culture embryos in the petri dish, that you do lose imprints of some of the very sensitive genes, and one of the genes is IGF2, which is actually involved in B-W.  It depends on the media composition.  In the mouse, it’s the NaCl concentration that’s important.  And they even see imprinting defects after implantation.  So it is concerning that you might find this in humans.  The issue is that when the embryo is out of the mother and in culture for a couple days under certain medium conditions, you have to worry that you may lose some imprinting on very sensitive genes.  We would like to understand how to avoid this, but you can’t experiment with human embryos. Any study to do this would be very difficult and challenging.  But the incidence of this disease is very low.  You can look at the problem in mice but the results do not necessarily translate to humans.

SCP:
Please comment about your feelings as to the importance of public discussions and lectures regarding ESC research.  Are there ways in which you feel we should be educating and including the public in this important work? 

RJ:
This discussion is very important , as there is so much misconception in the public.  I think good science writers have an enormously important role here.  And not just with the public but also with legislators.  It’s amazing how much misinformation there is even among the  legislators. I’ve seen how these issues are discussed and misunderstood.  It’s a very important task for scientists working in this field to be available to inform the public and the legislature about the science and the facts.  And to get the facts out independently of ideology and other considerations.  
We have to take this obligation very seriously.

SCP:
How detrimental, in your opinion, is the fact that the policies on stem cell research are different in so many countries?    

RJ:
I think it very much depends on the country.  In Germany it’s a very contentious issue, and due to their history they have made strict embryo protection laws, which I think are very bad.  In the US there is no law at all.  But there is a ban on federal funding for this research.  I think this has shaped the public opinion.  But there are also some interesting cases with some very conservative senators who are anti-abortionists, but are also staunch supporters of embryonic stem cell research and therapeutic cloning.  I think it is because they see in their families or their friends the potential of this type of research for medicine.  And it immediately changes how they look at this.  So the opinion people have is very personally colored.

SCP:
What do you feel is one of the most important experiences or defining moments in your education, career, or life that has contributed to your success as a researcher?

RJ:
I think when I was a visiting fellow in Beatrice Mintz’s lab that was a most decisive experience for me. I was a postoc in Arnold Levine’s laboratory at the time and he was a very generous advisor.  He taught me how to work with SV-40 and taught me molecular biology, and when I went to Mintz’s lab for 9 months, I learned to think the way she was thinking about development and embryos, and began to combine it with the molecular biology I had learned in Arnold Levine’s lab.   This likely was the most important experience for my subsequent career.  When we injected the DNA into the embryos and made the first transgenic mice, and then when I saw the first mice being born I was blown away.  And they were all normal and we didn’t know what to do with them.  We couldn’t believe it that they might carry the injected DNA.  Importantly I had to figure out how to find the DNA if it was present. Southern blotting or PCR had not been invented yet, so I had to learn techniques such as Nick translation and cot curves to detect DNA sequences, and it took a long time to actually prove that these animals were indeed transgenic.

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