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3 posts from February 2010

February 26, 2010

Encouraging cell development to reduce the long-term impacts of heart failure

Heart failure is a serious yet relatively common condition that limits the ability of the human heart to properly supply the body with blood. The odds of heart failure increase as we age, so finding treatment options is becoming increasingly important as the population ages, particularly given the high cost of current heart failure treatment. However, ongoing research using stem cells seems to be opening doors for new treatment options.

Dr. Bernhard Kuhn, Associate in cardiology at Boston Children’s Hospital and Assistant Professor of paediatrics at Harvard Medical School, has been looking into the damage done during heart failure, and how naturally-occurring heart regeneration, which isn’t typically significant enough to reverse the damage, can be stimulated in order to encourage new heart cell development. What prompted Dr. Kuhn‘s research was the long-standing observation that some heart cells will re-enter the cell development cycle after a myocardial infarction (heart attack).

“Over the past 100 years, researchers have repeatedly found that some cardiomyocytes—heart muscle cells—in the border zone of the infarct re-enter the cell cycle,” Dr. Kuhn said during a February 8 presentation at the Ottawa Hospital Research Institute. “This was found repeatedly, and our work is based in part on that notion that there is some renewal and attempt to regenerate after myocardial infarction in an adult mammalian heart. It is not sufficient to induce clinically significant cardiac regeneration, but it suggests that some cardiomyocytes can be induced to re-enter the cell cycle. We are investigating this systematically with the goal of enhancing this process for therapeutic applications.”

Dr. Kuhn’s experiments began using neuregulin and periostin peptide, both extracellular proteins, to encourage cell development in rats which have suffered an infarction. What he found was that the injection of neuregulin did increase the number of heart cells. Subsequent tests confirmed that the heart became denser, rather than larger; that the new cells were fully differentiated and functional heart cells; and that the regeneration was sustained even after treatment, leading Dr. Kuhn to conclude that “neuregulin induces permanent, functional improvements.”

In moving forward in this pre-clinical research, Dr. Kuhn is looking to test his findings using larger animals, and different methods of treatment. Eventually, he hopes to determine how it might be used in human clinical trials in order to stem the progressive deterioration of the heart after heart failure.

February 17, 2010

DNA damage necessary for cell development

Canadian scientists have discovered that stem cells intentionally damage their own DNA in order to regulate development. The breakthrough findings clear up the mystery of how cell death proteins actually promote cell differentiation and cell development.

DNA damage during muscle cell differentiation The study, led by Dr. Lynn A. Megeney of the Ottawa Hospital Research Institute, published in the Proceedings of the National Academy of Science found that two cell-death proteins, caspase 3 and caspase activated DNase (CAD), previously thought of as damaging were actually performing a necessary maintenance function: namely, triggering cellular development. 

This may well change the focus of some current research which has sought to inhibit these death proteins in order to prevent cell damage. The hypothesis was that these cell-death proteins’ main function was to kill the cell, however, Megeney’s findings suggest that DNA damage is the penultimate step to cell differentiation, not necessarily to cell death. 

Megeney had always been puzzled by the presence of supposed cell-death proteins in single-celled organisms, such as yeast. “Why would a single-celled organism, which exists only to replicate, have a pathway whose sole purpose was to kill it? It makes perfect sense for a multi-cellular organism because there are things we want to get rid of but it defies logic in a single cell life form. To me, that suggested there were other functions going on.”

Numerous studies in recent years have shown that inhibiting caspase 3 also inhibits the development of the cell. What Megeney and his team found in this most recent study is that the DNA damage which is triggered by caspase 3 and CAD is critical to the development of the adult cell. The stem cells will intentionally cut and repair the DNA in order to activate genes that promote the development of new tissue. Megeney explains, “If you think about a stem cell versus an adult cell, a lot of things happen in the progression. You have to turn hundreds of genes on and hundreds of genes off in a very short timeframe to get adult cells. Controlled DNA damage is actually a great way to manage this process.” 

One question that arises from these findings is what happens when a cell’s DNA does not repair properly? Would it lead to a mutation of the cell and if so, could that mutation be passed on to the cell’s descendants? 

In response to these questions, Megeney’s current research seeks to map the DNA breaks that occur during the cell maturation process. “If we can map the breaks and determine how a cell uses these DNA breaks to spur development, then perhaps we can use this knowledge to push cell development in specific ways that could be useful for treating illness or disease.”


Photo: Red staining indicates areas of DNA damage in healthy muscle stem/progenitor cells under going differentiation.

 

February 11, 2010

Looking for clues to understand and treat progeria

The answers to many childhood diseases may be held deep within our cells. Dr. William Stanford, a stem cell researcher at the University of Toronto and co-Director of the Ontario Human iPS Facility, has been looking at the mechanisms that determine whether and how a stem cell will differentiate in hopes of finding treatments for a range of muscular and blood diseases. In a recent presentation at the Ottawa Hospital Research Institute, Dr. Stanford discussed his research surrounding Hutchinson-Gilford progeria syndrome [HGPS], a disorder that occurs in roughly one per eight million births.

As Dr. Stanford describes the disease:
“[HGPS] is the prototypical progeroid syndrome, where patients are born undistinguishable in the first year of life from normal children, but somewhere between age one and two years of age, they start developing this rapid aging disorder. [The]… median age of death is age 13, although a patient died just this past year at the age of 18, so they can live longer.”
HGPS has been shown to be linked to cellular mutation caused the cell’s inability to produce a protein known as lamin A. By aging cells in vitro, Dr. Stanford and his research team are trying to better understand the molecular triggers that regulate aberrant splicing of lamin A, which will enable them to “develop drug targets to establish a directed small molecule screen” and address the affected genetic material head-on.  The goal is to restrict the damage that’s done by the disease and slow down the progression of the disease, if not holding off the disease indefinitely. Dr. Stanford’s work is funded by the Progeria Research Foundation (PRF) and he will be presenting his latest findings a the PRF’s 10th Anniversary Workshop in April 2010.

More broadly, Dr. Stanford hopes that his work in HGPS will provide valuable information about cell networks that can be applied to other illnesses. “One of the reasons we are studying rare diseases is to pull them apart and to apply what we’ve learned to other, more common, diseases.”


About HPGS: The disease is characterized by aging of the skin, hair and fatty tissue loss, atherosclerosis and cardiovascular disease. Although HPGS disease is rare, many children affected by it have been brought together by the PRF for clinical drug trials, and some have personal web sites documenting how they and their families go about their daily lives dealing with progeria.