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Researchers safely regenerate failing mouse hearts with programmed embryonic stem cells
February 28, 2007ROCHESTER, Minn. — Mayo Clinic researchers have safely transplanted cardiac preprogrammed embryonic stem cells into diseased hearts of mice successfully regenerating infarcted heart muscle without precipitating the growth of a cancerous tumor — which, so far, has impeded successful translation into practice of embryonic stem cell research.
The Mayo study is the first known report establishing a successful, tumor-resistant approach to growing new heart tissue from an embryonic stem cell source. The study is published in the February issue of the Journal of Experimental Medicine.
Embryonic stem cells have the potential to become any cell type in the body. But directing the stem cells to regenerate targeted tissue is a process that hasn't yet been perfected. Scientists continue to closely scrutinize stem cell strategies to establish even safer and more effective treatments for disease.
"Embryonic stem cells are like a stealth fighter jet that flies virtually undetectable by radar," says the study's first author, Atta Behfar, M.D., Ph.D., a clinician-investigator fellow in the Mayo Graduate School of Medicine. "The host body doesn't recognize embryonic stem cells, which it allows to multiply freely in an unimpeded fashion."
The Mayo study is the first known report of a successful strategy for programming embryonic stem cells to suppress cancer genes, to mature into heart cells (also known as cardiomyocytes) and to successfully fix injured hearts without causing tumors to develop. The study removes a critical obstacle towards translation of regenerative technology into developing new therapies for people with heart disease.
"Embryonic stem cells have an unequaled potential for repair, yet it has been uncertain whether we can drive them to safely regenerate the tissue we would like to replace," says Andre Terzic, M.D., Ph.D., a stem cell specialist and lead investigator of the study. "Our objective was to repair heart muscle by avoiding the limitations intrinsic to embryonic stem cells, i.e., potential tumor growth.
"In this study, we have successfully programmed embryonic stem cells to safely generate new cardiac muscle tissue, leading potentially to new therapy," Dr. Terzic says.
The Study
Researchers transplanted mouse embryonic stem cells into infarcted hearts of mice. Consistent with the risk for uncontrolled growth, a significant number of recipient mouse hearts developed tumors. To avoid tumor formation, researchers secured guided differentiation of stem cells to produce cardiopoietic cells, or cardiac specified cell precursors rather than any cell type. Treatment with cardiopoietic cells proved to have no tendency to develop into cancer. Tumor-free heart repair occurred in all treated mice. Two months after cardiopoietic stem cell transplantation, scientists reported a 35 percent improved output in treated hearts.
The threat of tumor growth associated with embryonic stem cell transplants was eliminated by restricting expression of oncogenes and pluripotency genes through transgenic manipulation of tumor necrosis factor alpha (TNFa), a genome reprogramming protein. Researchers found that over-expressed TNFa promoted guided control of cardiac embryonic stem cells to drive the cardiogenesis process.
Researchers discovered approximately 15 proteins whose production was dramatically increased after TNFa stimulation. These proteins, when combined into a "cocktail," secured guided differentiation of embryonic stem cells, producing cardiac progenitors called cardiopoietic cells. Such guided heart precursor cells did not form tumors, even though they were transplanted at doses that would otherwise carry a high risk for tumorigenesis with embryonic stem cells.
"Our goal is to apply these findings to adult stem cells, and in our next step create the first human cardioprogenitor stem cells as a tool for therapies in the future," Dr. Terzic says.
Mayo Clinic
"Embryonic stem cells are like a stealth fighter jet that flies virtually undetectable by radar," says the study's first author, Atta Behfar, M.D., Ph.D., a clinician-investigator fellow in the Mayo Graduate School of Medicine. "The host body doesn't recognize embryonic stem cells, which it allows to multiply freely in an unimpeded fashion."
The Mayo study is the first known report of a successful strategy for programming embryonic stem cells to suppress cancer genes, to mature into heart cells (also known as cardiomyocytes) and to successfully fix injured hearts without causing tumors to develop. The study removes a critical obstacle towards translation of regenerative technology into developing new therapies for people with heart disease.
"Embryonic stem cells have an unequaled potential for repair, yet it has been uncertain whether we can drive them to safely regenerate the tissue we would like to replace," says Andre Terzic, M.D., Ph.D., a stem cell specialist and lead investigator of the study. "Our objective was to repair heart muscle by avoiding the limitations intrinsic to embryonic stem cells, i.e., potential tumor growth.
"In this study, we have successfully programmed embryonic stem cells to safely generate new cardiac muscle tissue, leading potentially to new therapy," Dr. Terzic says.
The Study
Researchers transplanted mouse embryonic stem cells into infarcted hearts of mice. Consistent with the risk for uncontrolled growth, a significant number of recipient mouse hearts developed tumors. To avoid tumor formation, researchers secured guided differentiation of stem cells to produce cardiopoietic cells, or cardiac specified cell precursors rather than any cell type. Treatment with cardiopoietic cells proved to have no tendency to develop into cancer. Tumor-free heart repair occurred in all treated mice. Two months after cardiopoietic stem cell transplantation, scientists reported a 35 percent improved output in treated hearts.
The threat of tumor growth associated with embryonic stem cell transplants was eliminated by restricting expression of oncogenes and pluripotency genes through transgenic manipulation of tumor necrosis factor alpha (TNFa), a genome reprogramming protein. Researchers found that over-expressed TNFa promoted guided control of cardiac embryonic stem cells to drive the cardiogenesis process.
Researchers discovered approximately 15 proteins whose production was dramatically increased after TNFa stimulation. These proteins, when combined into a "cocktail," secured guided differentiation of embryonic stem cells, producing cardiac progenitors called cardiopoietic cells. Such guided heart precursor cells did not form tumors, even though they were transplanted at doses that would otherwise carry a high risk for tumorigenesis with embryonic stem cells.
"Our goal is to apply these findings to adult stem cells, and in our next step create the first human cardioprogenitor stem cells as a tool for therapies in the future," Dr. Terzic says.
Mayo Clinic
Stem Cells Current Events and Stem Cells News RSSNew discovery about the formation of new brain cells
The generation of new nerve cells in the brain is regulated by a peptide known as C3a, which directly affects the stem cells' maturation into nerve cells and is also important for the migration of new nerve cells through the brain tissue, reveals new research from the Sahlgrenska Academy published in the journal Stem Cells.
Umbilical cord blood stem cell transplant may help lung, heart disorders
Two separate studies published in the current issue of Cell Transplantation (18:8), - now freely available on-line have shown that transplanted human-derived umbilical cord blood (UCB) stem cells transplanted in an animal model had positive therapeutic effects on specific lung and heart disorders the animal models.
Gene mismatch influences success of bone marrow transplants
A commonly inherited gene deletion can increase the likelihood of immune complications following bone marrow transplantation, an international team of researchers reports in the November 22 advance online issue of Nature Genetics.
New research shows versatility of amniotic fluid stem cells
For the first time, scientists have demonstrated that stem cells found in amniotic fluid meet an important test of potential to become specialized cell types, which suggests they may be useful for treating a wider array of diseases and conditions than scientists originally thought.
First reconstitution of an epidermis from human embryonic stem cells
Stem cell research is making great strides. This is yet again illustrated by a study carried out by the I-STEM* Institute (I-STEM/ Inserm UEVE U861/AFM), published in the Lancet on 21 November 2009. The I-STEM team, directed by Marc Peschanski has just succeeded in recreating a whole epidermis from human embryonic stem cells.
Bone Implant Offers Hope for Skull Deformities
A synthetic bone matrix offers hope for babies born with craniosynostosis, a condition that causes the plates in the skull to fuse too soon.
Your Own Stem Cells Can Treat Heart Disease
The largest national stem cell study for heart disease showed the first evidence that transplanting a potent form of adult stem cells into the heart muscle of subjects with severe angina results in less pain and an improved ability to walk. The transplant subjects also experienced fewer deaths than those who didn't receive stem cells.
Is hepatic differentiation of embryonic stem cells induced by valproic acid and cytokines?
Embryonic stem (ES) cells, known for their capacity to proliferate indefinitely and differentiate into almost all types of cells including hepatocytes, have raised the hope of cellular replacement therapy for liver failure.
Paradoxical protein might prevent cancer
One difficulty with fighting cancer cells is that they are similar in many respects to the body's stem cells. By focusing on the differences, researchers at Karolinska Institutet have found a new way of tackling colon cancer. The study is presented in the prestigious journal Cell.
U of M researchers find 2 units of umbilical cord blood reduce risk of leukemia recurrence
A new study from the Masonic Cancer Center, University of Minnesota shows that patients who have acute leukemia and are transplanted with two units of umbilical cord blood (UCB) have significantly reduced risk of the disease returning.
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