Category Archives: Stem Cells

SAN DIEGO Researchers at the University of California, San Diego School of Medicine have discovered that hard-to-reach, drug-resistant leukemia stem cells (LSCs) that overexpress multiple pro-survival protein forms are sensitive and thus vulnerable to a novel cancer stem cell-targeting drug currently under development.

The findings, published in today's (Jan. 17) online issue of Cell Stem Cell, open the possibility that diseases like chronic myeloid leukemia (CML) and some solid tumor cancers might in combination with other therapies be more effectively treated with this drug, and with a lower chance of relapse.

Led by principal investigator Catriona H. M. Jamieson, M.D., Ph.D., associate professor of medicine and director of stem cell research at UC San Diego Moores Cancer Center, the researchers found that a compound called sabutoclax appears to selectively target LSCs that express particular protein isoforms through alternatively splicing, a fundamental process in which a gene is able to code for multiple proteins.

Jamieson and colleagues found that alternative splicing of BCL2 genes, which code for proteins involved in apoptosis or programmed cell death, specifically promoted malignant transformation of dormant white blood cell precursors into "blast crisis" LSCs. The blast crisis is the final phase of CML when overabundant, abnormal white blood cells crowd out healthy cells, causing serious dysfunction.

Of clinical importance, they noted that sabutoclax, which suppresses all BCL2 anti-apoptotic proteins, renders these marrow-dwelling blast crisis LSCs sensitive and more susceptible to TKI-based therapeutics at doses that do not harm normal progenitor cells.

"Our findings show that pan-BCL2 inhibition will be critical for the eradication of cancer stem cells in CML and that there is an essential link between cancer stem cell dormancy, pro-survival BCL2 isoform expression and therapeutic resistance," Jamieson said. "By using a novel pan-BCL2 inhibitor, we may be able to prevent therapeutic resistance by sensitizing malignant stem cell clones to TKIs."

The findings may have implications for treating solid tumor cancers, such as colon, prostate, breast, and brain cancers, noted Daniel J. Goff, the study's first author. "With many of these tumor types being shown to harbor cancer stem cells, it raises the question of whether BCL2 family expression as well as isoform-switching may be crucial for the maintenance of cancer stem cells in these diseases as well," he said. "If so, they may also be candidates for treatment with a BCL2 inhibitor like sabutoclax."

Co-authors are Angela Court Recart, Anil Sadarangani, Heather Leu, Janine Low-Marchelli, Wenxue Ma, Alice Y. Shih, Ifat Geron, Minya Pu, Lei Bao, Ryan Chuang, Larisa Balaian, Peggy Wentworth, Kristen M. Smith, Christina A.M. Jamieson, Sheldon R. Rorris and Karen Messer, UC San Diego Department of Medicine and UC San Diego Moores Cancer Center; Hye-Jung Chun and Marco Marra, Michael Smith Genome Sciences Center, Vancouver, B.C., Canada; Christian L. Barrett and Kelly A. Frazer, UC San Diego Department of Pediatrics; Maryla Krajewska, Jun Wei, Dayong Zhai, Maurizio Pellecchia and John C. Reed, Sanford-Burnham Medical Research Institute; Jason Gotlib, Stanford Medical Center; Mark Minden, Princess Margaret Hospital, Toronto, Canada; Giovanni Martinelli, Institute of Hematology and Medical Oncology, University of Bologna, Italy; Jessica Rusert and Lawrence S.B. Goldstein, UC San Diego Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute; Kim-Hien Dao, Oregon Health and Science University, Portland; Kamran Shazand and Thomas J. Hudson, Ontario Institute for Cancer Research, Toronto, Canada.

Funding for this research was provided by a California Institute for Regenerative Medicine (CIRM) early Translational II grant (TR2-1789), a CIRM HALT leukemia disease team grant (DR1-01430), the UCSD CIRM Training Grant (TG2-01154), the Ratner Family Foundation, the National Cancer Institute (CA-55164), the National Institutes of Health (CA-149668), the Ontario Institute for Cancer Research, Genome Canada, Ontario Genomics Institute and the Canadian Institute of Health Research.

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Drug targets leukemia stem cells

Mouse nervous-system cells (green), hijacked and turned by leprosy bacteria into stem cells, attack muscle fibre (red).

Rambukkana Lab members

Leprosy bacteria can reprogram cells to revert to a stem-cell-like state, able to mature into different cell types, researchers report today in Cell1.

The scientists stumbled on the discovery while researching the way leprosy spreads around the body. The mechanism of the hijacking is unclear, but reproducing it could lead to new stem-cell-based therapeutic strategies.

The initial target of the leprosy bacterium Mycobacterium leprae is Schwann cells, which are part of the peripheral nervous system. Like rubber around an electric wire, the cells wrap around nerves to insulate the electric signals passing through.

The researchers isolated Schwann cells from mice and infected them with M. leprae. The bacteria reprogrammed the cells into a stem-like state, turning off genes associated with mature Schwann cells and turning on embryonic or developmental ones.

The bacteria appeared to trigger Schwann cells' plasticity, the ability to revert to an immature state and turn into new types of cells. (Healthy Schwann cells do so to help nerves recover and regenerate after an injury.)

This is a very sophisticated mechanism it seems that the bacterium knows the mechanistic interaction of the Schwann cell better than we do, says Anura Rambukkana, a regeneration biologist at the University of Edinburgh, UK, who led the study.

Once reprogrammed, the stem cells are able to migrate to different body areas, and the bacteria ride along. When the infected cells reach another tissue, such as skeletal muscle, they integrate with that tissue's cells, spreading the bacteria. The infected stem cells were also found to attract immune cells by secreting proteins called chemokines allowing the bacteria to hitch a ride on these cells as well.

The researchers do not know what triggers the reprogramming event, but they suspect that the mechanism could exist in other infectious diseases.

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Leprosy bug turns adult cells into stem cells

Newswise Researchers at the University of California, San Diego School of Medicine have discovered that hard-to-reach, drug-resistant leukemia stem cells (LSCs) that overexpress multiple pro-survival protein forms are sensitive and thus vulnerable to a novel cancer stem cell-targeting drug currently under development.

The findings, published in the January 17 online issue of Cell Stem Cell, open the possibility that diseases like chronic myeloid leukemia (CML) and some solid tumor cancers might in combination with other therapies be more effectively treated with this drug, and with a lower chance of relapse.

Led by principal investigator Catriona H. M. Jamieson, MD, PhD, associate professor of medicine and director of stem cell research at UC San Diego Moores Cancer Center, the researchers found that a compound called sabutoclax appears to selectively target LSCs that express particular protein isoforms through alternatively splicing, a fundamental process in which a gene is able to code for multiple proteins.

An emerging class of drugs called tyrosine kinase inhibitors (TKI) such as imitinib (Gleevec), gifitinib (Iressa) and sunitinib (Sutent) has become a popular anti-cancer treatment. However, current TKIs are not 100 percent effective. In cases of CML, for example, some LSCs tucked protectively within bone marrow elude destruction, develop resistance to therapy, self-renew and eventually cause the leukemia to dramatically return.

Jamieson and colleagues found that alternative splicing of BCL2 genes, which code for proteins involved in apoptosis or programmed cell death, specifically promoted malignant transformation of dormant white blood cell precursors into blast crisis LSCs. The blast crisis is the final phase of CML when overabundant, abnormal white blood cells crowd out healthy cells, causing serious dysfunction.

Of clinical importance, they noted that sabutoclax, which suppresses all BCL2 anti-apoptotic proteins, renders these marrow-dwelling blast crisis LSCs sensitive and more susceptible to TKI-based therapeutics at doses that do not harm normal progenitor cells.

Our findings show that pan-BCL2 inhibition will be critical for the eradication of cancer stem cells in CML and that there is an essential link between cancer stem cell dormancy, pro-survival BCL2 isoform expression and therapeutic resistance, Jamieson said. By using a novel pan-BCL2 inhibitor, we may be able to prevent therapeutic resistance by sensitizing malignant stem cell clones to TKIs.

The findings may have implications for treating solid tumor cancers, such as colon, prostate, breast, and brain cancers, noted Daniel J. Goff, the studys first author. With many of these tumor types being shown to harbor cancer stem cells, it raises the question of whether BCL2 family expression as well as isoform-switching may be crucial for the maintenance of cancer stem cells in these diseases as well, he said. If so, they may also be candidates for treatment with a BCL2 inhibitor like sabutoclax.

Co-authors are Angela Court Recart, Anil Sadarangani, Heather Leu, Janine Low-Marchelli, Wenxue Ma, Alice Y. Shih, Ifat Geron, Minya Pu, Lei Bao, Ryan Chuang, Larisa Balaian, Peggy Wentworth, Kristen M. Smith, Christina A.M. Jamieson, Sheldon R. Rorris and Karen Messer, UCSD Department of Medicine and UCSD Moores Cancer Center; Hye-Jung Chun and Marco Marra, Michael Smith Genome Sciences Center, Vancouver, BC, Canada; Christian L. Barrett and Kelly A. Frazer, UCSD Department of Pediatrics; Maryla Krajewska, Jun Wei, Dayong Zhai, Maurizio Pellecchia and John C. Reed, Sanford-Burnham Medical Research Institute; Jason Gotlib, Stanford Medical Center; Mark Minden, Princess Margaret Hospital, Toronto, Canada; Giovanni Martinelli, Institute of Hematology and Medical Oncology, University of Bologna, Italy; Jessica Rusert and Lawrence S.B. Goldstein, UCSD Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute; Kim-Hien Dao, Oregon Health and Science University, Portland; Kamran Shazand and Thomas J. Hudson, Ontario Institute for Cancer Research, Toronto, Canada.

Funding for this research was provided by a California Institute for Regenerative Medicine (CIRM) early Translational II grant (TR2-1789), a CIRM HALT leukemia disease team grant (DR1-01430), the UCSD CIRM Training Grant (TG2-01154), the Ratner Family Foundation, the National Cancer Institute (CA-55164), the National Institutes of Health (CA-149668), the Ontario Institute for Cancer Research, Genome Canada, Ontario Genomics Institute and the Canadian Institute of Health Research.

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Drug Targets Hard-to-Reach Leukemia Stem Cells Responsible for Relapses

SAN DIEGO, Jan. 14, 2013 /PRNewswire-USNewswire/ -- Apparent stem cell transplant success in mice may hold promise for people with amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. The results of the study will be presented at the American Academy of Neurology's 65th Annual Meeting in San Diego, March 16 to 23, 2013.

"There have been remarkable strides in stem cell transplantation when it comes to other diseases, such as cancer and heart failure," said study author Stefania Corti, MD, PhD, with the University of Milan in Italy and a member of the American Academy of Neurology. "ALS is a fatal, progressive, degenerative disease that currently has no cure. Stem cell transplants may represent a promising avenue for effective cell-based treatment for ALS and other neurodegenerative diseases."

For the study, mice with an animal model of ALS were injected with human neural stem cells taken from human induced pluripotent stem cells (iPSCs). iPSC are adult cells such as skin cells that have been genetically reprogrammed to an embryonic stem cell-like state. Neurons are a basic building block of the nervous system, which is affected by ALS. After injection, the stem cells migrated to the spinal cord of the mice, matured and multiplied.

The study found that stem cell transplantation significantly extended the lifespan of the mice by 20 days and improved their neuromuscular function by 15 percent.

"Our study shows promise for testing stem cell transplantation in human clinical trials," said Corti.

The study was supported by AriSLA - The Italian Foundation for Research on Amyotrophic Lateral Sclerosis (ALS).

Learn more about ALS at http://www.aan.com/patients.

The American Academy of Neurology, an association of more than 25,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer's disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson's disease and epilepsy.

For more information about the American Academy of Neurology, visit http://www.aan.com or find us on Facebook, Twitter, Google+ and YouTube.

SOURCE American Academy of Neurology

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Stem Cells May Hold Promise for Lou Gehrig's Disease (ALS)

SYDNEY, AUSTRALIA--(BUSINESS WIRE)--

Genea Stem Cells Pty Ltd (GSC), a supplier and developer of disease-specific human stem cells, today announced that 25 of its disease specific embryonic pluripotent stem cell lines have been placed on the USA National Institutes of Health (NIH) human stem cell registry. These embryonic stem cell lines are now all available commercially for use in medical research.

These cell lines include one disease free pluripotent cell line and 24 others with individual mutations that give rise to several severe diseases such as cancer (breast cancer, Wilms tumor and Von HippelLindau syndrome), Huntingtons disease, muscular dystrophy (including CMT, FSHD and Myotonic) and cystic fibrosis as well as some rarer genetic diseases such as Trisomy 5, macular dystrophy, incontinentia pigmenti, juvenile retinoschisis, alpha thalassemia and autosomal dominant torsion dystonia. All these cell lines are genetically unmodified and have been derived in compliance with international regulatory and ethical guidelines.

GSC has the worlds largest private bank of pluripotent human embryonic stem cells with more than 100 individual lines expressing almost 30 different genetic diseases. The Company is also developing multiple differentiated cell lines from these pluripotent lines and currently offer GABAergic neurons and vascular smooth muscle cells. These are the only commercially available differentiated disease affected cell lines in the world and GSC is willing to work with drug developers globally to custom-make disease-specific differentiated cell lines for use in in vitro research.

Dr Uli Schmidt, General Manager of GSC, commented: It is a tribute to all the hard work and diligence of our scientists in Sydney that so many of our lines have been accepted by the NIH. We believe that this year will see substantial commercial take up of these perfect in vitro research tools.

GSC will be exhibiting (booth 1536) this week at the Society for Lab Automation and Screening (SLAS) 2013 conference and exhibition in Orlando, Florida. [12-16 January 2013].

- ends -

About Genea Stem Cells

Genea Stem Cells (GSC) supplies and develops disease-specific pluripotent and differentiated human embryonic stem cells for use in drug development and research. All of our cellular products are genetically unmodified human cells - the most accurate in vitro reflection of clinical conditions, promising more predictive disease models and thereby reducing the need for animal studies. GSC provides the following products for use in drug development and medical research:

As well as providing the above products, GSC also works collaboratively with industry for custom-developed cell-based assay solutions in drug development.

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Genea Stem Cells (GSC): 25 New Disease Specific Pluripotent Stem Cell Lines Placed On The NIH Registry

Researchers are keen to compare induced pluripotent stem cells (pictured) with their embryonic cousins.

SILVIA RICCARDI/SPL

The US Supreme Courts decision last week to throw out a lawsuit that would have blocked federal funding of all research on human embryonic stem cells cleared the gloom that has hung over the field for more than three years. Yet the biggest boost from the decision might go not to work on embryonic stem (ES) cells, but to studies of their upstart cousins, induced pluripotent stem (iPS) cells, which are created by reprogramming adult cells into a stem-cell-like state.

At first glance, iPS-cell research needs no help. Researchers flocked to the field soon after a recipe for deriving the cells from adult mouse cells was announced in 2006, partly because this offered a way to skirt the thorny ethical issues raised by extracting cells from human embryos. But the real allure of iPS cells was the promise of genetically matched tissues. Adult cells taken from a patient could be used to create stem cells that would, in turn, generate perfectly matched specialized tissues replacement neurons, say for cell therapy. Although the number of published papers from iPS-cell research has not yet caught up with that of ES-cell work (see Inducing a juggernaut), US funding for each approach is now roughly matched at about US$120 million a year.

C. T. Scott et al. Cell 145, 820826 (2011)

But, as iPS cells crop up in ever more labs, ES cells generally cheaper, better behaved and backed by an extra decades worth of data promise to have an important supporting role. Ever since iPS cells were described, researchers have been trying to understand just how similar they are to ES cells. iPS cells begin with different patterns of gene expression, and they can also acquire mutations during the reprogramming process, which means that every iPS cell must be thoroughly evaluated before it can be used in any study. Human ES cells will always be the standard to which other cells will be compared, says Roger Pedersen, who studies how stem cells retain embryo-like states at the University of Cambridge, UK.

Federally supported ES-cell research was shut down in the United States on 23August 2010, a year after a lawsuit was filed by two opponents of human ES-cell research, and remained frozen for more than two weeks (see Fifteen years of controversy). Many investigators shied away from the field for fear of having to shut down again. The Supreme Courts move has reassured investigators such as Candace Kerr, who studies early development of the brain at the University of Maryland School of Medicine in Baltimore. As a young scientist working towards tenure, she felt particularly vulnerable to the threat of ES-cell funding being stopped. So she switched to iPS cells in 2010, while the lawsuit was working its way through the US court system. With the litigation over, she says she need not hesitate or fear adding to her work with experiments using ES cells, which she finds much easier to prompt into neurons than iPS cells. I am excited and relieved by this decision, she says.

The tussles over whether or not US federal funds can be used for research involving human embryonic stem cells have a long history.

November 1998 Paper announces the isolation of embryonic stem (ES) cells from human embryos.

August 2001 US President George W. Bush restricts federal funding for work on human ES cells to a few extant lines.

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Court lifts cloud over embryonic stem cells