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Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Autoimmune Enteropathy

Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Autoimmune Enteropathy Independently of Regulatory T Cells

Biju Parekkadana,b, Arno W. Tillesa, Martin L. Yarmusha,b

ABSTRACT

Cell-based tolerogenic therapy is a relatively new approach for the treatment of autoimmune diseases. Mesenchymal stem cells (MSCs) have been shown to be potent immunomodulatory agents in a number of experimental and clinical scenarios; however, their use in various autoimmune diseases is undefined. Herein, we report the efficacy of MSC transplantation in a multiorgan autoimmunity model. Mice with defective peripheral tolerance caused by a deficiency in regulatory T cells were used as a testbed for therapy. After screening multiple target tissues of autoimmune attack, we observed an MSC-specific improvement in the histopathology of the distal ileum of treated mice. We then showed that MSCs can reduce mesenteric lymph node (MLN) cellularity in autoimmune mice during active disease and decrease activated T-cell populations in the MLN. Trafficking studies using enhanced green fluorescent protein (eGFP)-reporter MSCs revealed no appreciable engraftment in the intestine, but it did reveal the presence of eGFP+ cells organized in clusters within the MLN, as well as ancillary nodes. Semiquantitative analysis showed no difference in the number of clusters; however, eGFP+ cells in MLNs compared with ancillary nodes had distinct fibroblastoid morphology and formed a network with neighboring eGFP+ cells. Finally, we show evidence that transplantation of MSCs caused global immunosuppression, as measured by increased CD4+ CD8+ thymocyte production and serum interleukin-10 and decreased serum interferon-gamma. These data implicate the intestine as a new site of MSC tolerance induction and should motivate additional studies evaluating the use of MSCs as a treatment for autoimmune enteropathies.

 

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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.

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