Stem Cell Research by CIRM Grantees
- Understanding stem cell biology
Genetic Factors Found to Speed Embryonic Stem Cell Division
- CIRM authors: Yangming Wang, Robert Blelloch
- Researchers at UC, San Francisco developed a novel way of finding out the role of DNA-relatives called microRNA. These molecules are known to turn genes on and off and appear to regulate whether embryonic stem cells remain as stem cells or develop into mature cell types, but learning which genes are controlled by each microRNA has been a challenge. Using this screen, the researchers found 14 microRNAs that speed up cell division; of those, five are commonly found in human embryonic stem cells. It turns out these microRNAs deactivate genes that slow the cell cycle, essentially releasing the brakes on cell division. Identifying the role of these and other microRNAs could help researchers understand how to hold embryonic stem cells in their immature state, guide how those cells mature, or even develop treatments for cancer.
- Related Information: Nature Genetics paper, Press release, UCSF Institute for Regeneration Medicine, Funding grant summary, Blelloch bio
- Control of stem cell fate
Protein found to direct embryonic stem cells as they mature
- CIRM-funded author: Roel Nusse
- Researchers at the Stanford University School of Medicine have found that clusters of embryonic stem cells in a lab dish share some unexpected similarities with actual embryos. These clumps, called embryoid bodies, consist of hundreds of cells, many of which begin to form more mature cell types. For example, they often contain groups of primitive heart muscle cells that beat visibly. In this work, which was published in the November 6, 2008 issue of Cell Stem cell, the researchers found that the embryoid bodies also contain a line of cells that resemble an embryonic structure called the primitive streak. This streak is the first indication that the embryo has a top and bottom or back and front. Blocking molecules found in the embryoid body primitive streak pushed those cells to form a group of cells that make up skin and nerves. Enhancing those molecules pushed the cells to form cell types like muscle and intestine. This work could help researchers learn how to push embryonic stem cells to form particular cell types, which is a necessary step in developing stem cell-based therapies.
- Related Information: Cell Stem Cell paper, Press release, Stanford Stem Cell Biology and Regenerative Medicine Institute, Funding grant summary, Nusse lab page
- Heart disease
Embryonic stem cells repair heart damage in mice
- CIRM-funded authors: Joseph Wu, Micha Drukker, Irving Weissman, Robert Robbins
- Researchers at the Stanford University School of Medicine found that cells derived from human embryonic stem cells could repair damage in a mouse model of heart attack. The researchers first looked at which genes were active at every stage between the human embryonic stem cells and early heart muscle cells. The cells they implanted mirrored the genes that are active in the hearts of 20 week old fetal mice. After injecting the cells into the heart of a mouse with an induced heart attack, they found that the cells incorporated into the heart and significantly improved the heart’s ability to pump blood. This work, which appeared in the October 22, 2008 issue of PLoS ONE, could lead to new stem cell-based therapies for repairing damaged heart tissue
- Related Information: PLoS ONE paper, Stanford Stem Cell Biology and Regenerative Medicine Institute, Funding grant summary, Wu bio page
- Heart disease
Genetic Factor Enables Immature Cells to Form Normal Heart Tissue
- CIRM author: Deepak Srivastava
- Researchers at the Gladstone Institute for Cardiovascular Disease found a genetic factor that helps in the earliest stages of heart development as the primitive tube loops around on itself and forms the separate chambers. This factor -- a short relative of DNA called microRNA -- has an identical counterpart in humans, leading the researchers to believe that their work in fish is likely to relate directly to human heart development. When the researchers interfered with this microRNA while the heart was developing, the immature heart muscle cells failed to mature and the heart chambers didn’t form normally. These heart muscle precursors are a stage in between the embryonic stem cell and the mature heart muscle cell. The heart is among the first organs to develop and also the most critical. When the heart doesn’t develop properly the embryo dies. What’s more, common birth defects involve abnormalities in how these chambers form. Understanding all the steps between an embryonic stem cell and the mature heart cell could help researchers prevent or treat birth defects of the heart. The work was published in the October 27, 2008 issue of the Proceedings of the National Academy of Sciences.
- Related Information: Press release, Gladstone Institute of Cardiovascular Disease, Funding grant summary, Srivastava bio
- Cancer
Cancer-Fighting Proteins Have Dual Role in Helping Stem Cells Divide
- CIRM authors: Julien Sage, Irving Weissman, Emmanuelle Passegue
- Researchers at the Stanford University School of Medicine found that a group of well-known cancer-fighting proteins also help blood-forming stem cells divide normally. This is the first time the group of proteins known as the retinoblastoma family has been linked to stem cell function. Previously, they were known to help prevent the formation of many different kinds of tumors. The researchers found that when three proteins in the retinoblastoma family are absent, blood-forming stem cells in the bone marrow divide more often and primarily just form one of the two major types of cells in the blood system. The work, which was published in the October 9, 2008 issue of Cell Stem Cell, is the first to link these cancer-preventing proteins with stem cell function. The work could help clarify how the proteins prevent tumors from forming in tissue-specific stem cells such as those found in the bone marrow.
- Related Information: Cell Stem Cell paper, Press release, Stanford Stem Cell Biology and Regenerative Medicine Institute, Funding grant summary, Sage lab page
- Understanding stem cell biology
Molecule Found to Hold Stem Cells in Embryonic State
- CIRM-funded author: Dennis Clegg
- Researchers at UC, Santa Barbara discovered a growth factor that helps human embryonic stem cells thrive in the lab. These cells normally do not divide quickly and are prone to losing their embryonic state, maturing into tissue types such as muscle, heart, or nerve cells. Researchers working with the cells have been looking for factors that can be added to stem cell’s environment that will hold the cells in an immature state. These researchers found that a protein commonly found on the surface of mature cells, called MUC1, is found in an altered form, which they call MUC1*, on embryonic stem cells. Adding a factor that recognizes and latches on to the MUC1* protein holds the cells in the embryonic state. This work, which was published in the October 3, 2008 issue of PLoS ONE, will help researchers grow the large volumes of embryonic stem cells that will be needed for stem cell-based therapies.
- Related Information: PLoS ONE paper, UC, Santa Barbara Center for Stem Cell Biology and Engineering, Funding grant summary
- Understanding stem cell biology
Genetic Profile Distinguishes Types of Stem Cells
- CIRM-funded author: Louise Laurent
- Researchers at the The Scripps Research Institute found a new way of classifying the many cell types that fall under the category of “stem cells.” The term stem cell refers to tissue specific stem cells found in mature tissues such as blood, brain, or muscle, which are restricted to forming only cells found in those tissues, as well as to embryonic stem cells that are broadly able to form all cells of the body. The term is also used to refer to the so-called induced pluripotent stem (iPS) cells that scientists can now create out of adult skin cell and that mimic embryonic stem cells in their ability to form a variety of cell types. In this work, published in the September 18, 2008 issue of Nature, the researchers discovered a set of genes that are always active in the pluripotent cells – whether they were iPS cells or embryonic stem cells. As more stem cell populations become available, the gene profile discovered in this study will help researchers distinguish those cells that are truly pluripotent from those that are more restricted in the cell types they are able to form.
- Related Information: Nature paper, Scripps news story, The Scripps Research Institute, Funding grant summary
- Neurobiology
True Location of Brain Stem Cells Discovered
- CIRM-funded author: Darius Gleason
- Researchers at UC, Irvine identified the true location of adult stem cells in the brain. Previous studies indicated that in mammals, adult neural stem cells originate in a region of the brain called the subventricular zone. In this study, the team found evidence that stem cells exist only in a region called the ependymal layer, which is adjacent to the subventricular zone. They also coaxed the ependymal stem cells to divide in adult rats displaying Parkinson's Disease-like symptoms. This work raises the possibility that manipulating cells of the ependymal cell layer could lead to stem cell therapies for neurological diseases. The study was published in the July, 2008 issue of Neuroscience.
- Related Information: UC, Irvine press release, Sue and Bill Gross Stem Cell Research Center, , Funding grant summary
- Understanding stem cell biology
Fly Stem Cells Create their Home
- CIRM-funded author: Leanne Jones
- Researchers at the Salk Institute or Biological Studies discovered that stem cells in the testes of fruit flies are able to generate their own support cells. This work in flies could help guide researchers hoping to understand the environment surrounding resident populations of human stem cells - called the niche. The niche is difficult to study in humans but is an area of great interest because any therapy based on transplanting stem cells into a tissue will require those cells to be paced in a niche where they will thrive. This work raises the possibility that some transplanted stem cells may be able to produce their own niche. The work was published in the July 20, 2008 advance online edition of Nature.
- Related Information: Nature paper, Salk press release, Salk Institute for Biological Studies, Funding grant summary, Jones bio
- Aging
Aging Muscles Inhibit Stem Cells, Prevent Repair
- CIRM-funded authors: Morgan Carlson, Irina Conboy
- Researchers at UC, Berkeley identified a signaling molecule that interferes with the ability of older skeletal muscle to regenerate. After injury, adult skeletal muscle regenerates by activating muscle stem cells that fuse with the existing muscle cells to repair the damage. This ability to regenerate diminishes with age, not because of a decline in the number of resident stem cells, but because stem cells in the older muscle don’t respond when damage occurs. It turns out that older muscles release molecules that actively inhibit the resident stem cells. In this study, the team identified one of those molecules and showed that interfering with that molecule’s function restores the ability of muscle in older mice to regenerate after injury. This research illustrates the potential for recruiting adult resident stem cells in tissue repair. This study was published in Nature advance online publications June 15, 2008.
- Related Information: Nature paper, Press release, Berkeley Stem Cell Center, Funding grant summary, Conboy bio
- Creating new stem cells
New Embryonic Stem Cell Lines Avoid Animal Products
- CIRM-funded authors: Shawn Chavez, Seung Kim, Renee Reijo Pera
- Researchers at Stanford University School of Medicine derived new human embryonic stem cell lines using minimal animal products. Although numerous groups have derived stem cell lines, most were generated in the presence of animal serum and animal-derived feeder cells. These animal products are a concern because they may cause the stem cells to produce an immune response when transplanted into humans and may induce biological changes especially to the genome. In this study, the team characterized six lines that were derived with minimal use of animal products. The researchers verified that the lines behave like normal ES cells in their ability to both self-renew and differentiate to the major cell types. These lines may be useful for future studies that help move the field toward clinical-grade cell therapy. This study is in the June, 2008 issue of Stem Cells and Development.
- Related Information: Stem Cells and Development paper, Stanford Stem Cell Biology and Regenerative Medicine Institute, Funding grant summary, Pera lab page
- Understanding stem cell biology
Pattern of Small Genetic Factors Found to Characterize Embryonic Stem Cells
- CIRM-funded author: Louise Laurent
- Researchers at The Scripps Research Institute discovered that human embryonic stem cells have a very specific signature when it comes to the regulators of their genes. MicroRNAs are very small, naturally occurring bits of genetic material. They don't code for specific proteins like genes do, but they regulate the activity of genes and turn on and off their protein production. In embryonic stem cells microRNAs are actively preventing the production of proteins that tell cells to differentiate into specific heart or bone tissue, for example, but are pushing hard on genes that result in self-renewal. The team hopes to use these microRNAs to reprogram any type of cell to become as pluripotent as embryonic stem cells and to do it more safely than current reprogramming called iPS. The study was published in the June, 2008 issue of the journal Stem Cells.
- Related Information: Stem Cells paper, Press release , The Scripps Research Institute, Funding grant summary
- Cancer
Mutation Revealed to Convert Blood Stem Cells to Cancer Stem Cells
- CIRM-funded researcher: Wei Guo
- Researchers at UC, Los Angeles discovered a series of mutations that can convert normal blood stem cells into cancer stem cells. It is believed that many types of cancer result from cancer stem cells created by such mutations. In this case the first mutation converted normal stem cells and then caused over expression of an oncogene, a cancer gene, resulting in a proliferation of leukemia stem cells and acute T-cell lymphoblastic leukemia in a mouse model. The team hopes that by studying these pathways they will find ways to block them with small molecule drugs and cure the often fatal disease. The study was published in the May 22, 2008 issue of Nature.
- Related Information: Nature paper, UCLA press release, The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, Funding grant summary
- Control of stem cell fate
Genetic Factors Found to Regulate Embryonic Stem Cell Maturation
- CIRM-funded authors: Yanging Wang, Robert Blelloch
- Researchers at UC, San Francisco identified a molecule that regulates differentiation of embryonic stem cells. In some cases, small molecules of the genetic material RNA have the ability to turn genes on and off rather than carrying out the normal RNA function of coding for proteins. These small RNAs, called micro RNA or miRNA, are thought to be one way the cell regulates genes that control how stem cells differentiate into mature cell types. In this study, the researchers created genetically altered mouse embryonic stem cells that lack the miRNA DGCR8. These cells did not respond properly to signals that would normally cause stem cells to differentiate into mature cell types. Even after the cells began differentiating they continued making proteins that are normally only found in embryonic stem cells. This work shows that miRNAs are key molecules to target for controlling ES cell differentiation, which is essential for developing safe protocols for stem cell-based therapies. The work was published in the March, 2008 issue of Nature Genetics.
- Related Information: Nature Genetics paper, UCSF Institute for Regeneration Medicine, Funding grant summary, Blelloch bio
- Heart disease
Genetic Factor Influences Heart Muscle Formation from Embryonic Stem Cells
- CIRM-funded authors: Kathey Ivey, Bruce Conklin, Deepak Srivastava
- Researchers at the Gladstone Institute for Cardiovascular Disease discovered how two specific tiny genetic factors called microRNAs influence the differentiation of embryonic stem cells into heart muscle. They found that the factors not only drive the versatile cells to become heart, but also actively prevent them from becoming other tissue such as bone adding to their potential to make therapy more specific and targeted for patients. The study is published March 6, 2008 in the journal Cell Stem Cell.
- Related Information: Cell Stem Cell paper, Press release, Gladstone Institute of Cardiovascular Disease, Funding grant summary, Srivastava bio
- Heart disease
Mutation Causing Cardiomyopathy Validated in Mouse Embryonic Stem Cells
- CIRM-funded authors: Weiwei Fan, Douglas Wallace
- Researchers at UC, Irvine used mouse embryonic stem cells to demonstrate that a specific mutation can cause cardiomyopathy, with a thickened heart wall, in the mouse. The team looked at the small DNA molecule located outside of the nucleus, so-called mitochondrial DNA, which we all inherit exclusively from our mothers. They also discovered that severe mutations in this mitochondrial DNA are readily eliminated from the mouse germ line in just four generations. They expect the method they used to become a robust research tool to study the impact of mutations on stem cells. The study was published in Science on February 15.
- Related Information: Science paper, Press release, Sue and Bill Gross Stem Cell Research Center, Funding grant summary
- Cancer
First clinical Trial Begins for a Therapy Enabled By CIRM Funding
- CIRM-funded author: Catriona Jamieson
- Researchers at UC, San Diego verified a suspect gene mutation in blood-forming stem cells was by itself necessary and sufficient to cause a class of severe blood diseases called myeloproliferative disorders. They then worked with a team of researchers from other academic institutions and from the San Diego pharmaceutical company TargeGen to conduct animal tests of a compound TargeGen had already isolated and shown to inhibit that same genetic pathway. As a result of this broad collaboration, human clinical trials for this potential therapy began in February, 2008.
- Related Information: UC San Diego press release, UCSD Stem Cell Initiative, Funding grant summary
- Creating new stem cells
Validation of Technique Inducing Skin Cells to become Pluripotent Stem Cells
- CIRM-funded authors: William Lowry, Rupa Sridharan, Amander Clark, Kathrin Plath
- Researchers at UC, Los Angeles succeeded in inducing skin cells to become pluripotent cells with genetic featured very much like embryonic stem cells. They verified work published during the completion of their project, which showed that the introduction of four specific genetic factors is sufficient to induce differentiated adult cells into reverting to an embryonic stem cell-like state. This was critical validation of a procedure that could lead to a new way of developing personalized cell lines for therapy. The findings were published in the February 26, 2008 issue of the Proceedings of the National Academy of Sciences.
- Related Information: PNAS paper, Press release, The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, Lowry funding grant summary, Sridharan funding grant summary, Lowry lab page
- Supporting technologies
Genes Identified as Unique to Specialized Colon Cells
- CIRM-funded author: Cynthia Kosinski
- Researchers at UC, San Francisco found nearly a thousand genes that are expressed differently in different parts of the colon. The colon is constantly renewed via its own stem cells and understanding how these genes are expressed differently as the cells specialize will help understand what happens when this goes wrong as in colon cancer. The Findings were published in the September 25, 2007 Proceedings of the National Academy of Sciences.
- Related Information: PNAS paper, UCSF Institute for Regeneration Medicine, Funding grant summary
- Neurobiology
Proteins Found that Guide Neuron Migration in Brain
- CIRM-funded authors: Laura Elias, Arnold Kriegstein
- Researchers at UC, San Francisco discovered that membrane proteins that form cell to cell connections also have an important role in controlling how neurons migrate in the brain. Understanding neuronal migration is a critical aspect of cell therapy in the nervous system, as replacement cells will need to be directed to their appropriate site of action. This research project is also an example of how funding work in one field moves along work in another. The membrane proteins highlighted in this report had previously been identified in some cancers, and these new observations in neurons provide rationale for targeting them in cancer therapy. The finding was featured as a Nature cover story on August 23, 2007.
- Related Information: Nature paper, Press release, UCSF Institute for Regeneration Medicine, Funding grant summary, Kriegstein bio
- Understanding stem cell biology
Genes Found that Characterize Embryonic Stem Cells
- CIRM-funded authors: Marcia Grskovic, Miguel Ramalho-Santos
- Researchers at UC, San Francisco identified a group of genes that are active in embryonic stem cells but not in more differentiated cells. They also developed a technique to find DNA regions that could be important for activating these genes, and identified a factor that directs the production of proteins from genes that contain these regulatory DNA regions. These studies will greatly inform research efforts that rely on maintaining a stem cell's ability to proliferate and to generate the many different cell types in a human body. Findings were published in the August 2007 PLoS Genetics.
- Related Information: PLoS Genetics paper, UCSF Institute for Regeneration Medicine, Funding grant summary, Ramalho-Santos bio
- Understanding stem cell biology
Key Protein Involved in Forming Nuclear Membrane after Division Found
- CIRM-funded author: Youngjun Kim
- Researchers at UC, San Diego found the function of a key protein involved in the cell cycle, the process by which a cell duplicates all its genes and divides. The protein is critical to the assembly of the membrane around the cell's nucleus. A fundamental understanding of the cell cycle is integral to advancing all cell-based therapies. The findings were published in the April 17, 2007 Proceedings of the National Academy of Sciences.
- Related Information: PNAS paper, UCSD Stem Cell Initiative, Funding grant summary
- Neurobiology
Neural Stem Cell Repair Mechanism in the Brain Revealed
- CIRM-funded author: Chay Kuo
- Researchers at UC, San Francisco found that proteins involved in the generation of neurons early in development also help neural stem cells produce neurons after birth. Furthermore, the researchers identified a self-repair mechanism in the brain that relies on these neural stem cells. Understanding how endogenous neural stem cells repair and remodel a mature brain is critical to successful stem cell therapy. The findings were published in the December 15, 2006 issue of Cell.
- Related Information: Cell paper, Press release, UCSF Institute for Regeneration Medicine, Funding grant summary
