> By manipulating a critical cell-to-cell signaling pathway, researchers at the University of Pennsylvania School of Medicine have successfully increased the number cells required for the normal development of right-sided structures in the heart, including the right ventricle.
> Penn scientists were able to increase the numbers of a cardiac stem cell population, called Isl-1 positive cardiac progenitors, in the developing embryo and in tissue grown in a culture dish by activating the Wnt pathway.
> The finding suggests a potential therapeutic strategy whereby influencing this pathway would be used to generate specialized heart cells to repair or replace cells damaged by cardiac disease.
> The research will be reported in the Journal of Clinical Investigation’s online edition on June 21, 2007 and will appear in the print edition on July 2, 2007.

(PHILADELPHIA) — By manipulating a critical cell-to-cell signaling pathway, researchers at the University of Pennsylvania School of Medicine have successfully increased the number cells required for the normal development of right-sided structures in the heart, including the right ventricle. Penn scientists were able to increase the numbers of a cardiac stem cell population, called Isl-1 positive cardiac progenitors, in the developing embryo and in tissue grown in a culture dish by activating the Wnt pathway.  The finding suggests a potential therapeutic strategy whereby influencing this pathway would be used to generate specialized heart cells to repair or replace cells damaged by cardiac disease.

The research will be reported in the Journal of Clinical Investigation’s online edition on June 21, 2007 and will appear in the print edition on July 2, 2007.
 
“This is the first evidence that the Wnt signaling pathway plays a crucial role in the generation of cells that can differentiate into functioning cardiac structures,” said Edward E. Morrisey, PhD, Associate Professor of Medicine and Cell and Developmental Biology and the senior author on the paper. “Our studies indicate a direct link between Wnt and a specific family of progenitor cells that transform themselves into critical structures in the heart during development.”

Although scientists know that the Isl-1 positive progenitor cells play an important role in the development of the right side of the heart including the right ventricle, the molecular pathways regulating these critical cells are poorly understood.  Isl-1 progenitors have been shown to have the capacity of self-renewal and to differentiate into specialized cells including cardiac myocytes and smooth muscle cells, thus exhibiting the characteristics of tissue specific stem cells.  Morrisey and his team first demonstrated that the Wnt signaling pathway is active in Isl-1 progenitors. 

The next step taken by the Penn researchers was to increase or decrease the activity of the Wnt pathway to increase or decrease the number of Isl-1 progenitors respectively, the first time this has been shown in a mouse model.  This resulted in the loss of the right ventricle, which Isl-1 progenitors contribute to, whereas the left ventricle, which Isl-1 progenitors do not contribute towards, was spared.

The scientists also noticed that in addition to an increase in the numbers of Isl-1 positive cells, there was also an increase in a class of growth factors that has been shown to act cooperatively with Wnt signaling to regulate progenitor cells in other tissues. Having determined that the class of proteins called Fibroblast Growth Factors or FGFs worked downstream from Wnt signaling, the Penn scientists went on to show that at least one of the FGF ligands, FGF10, known to directly impact the development of the heart, was a direct target of Wnt signaling.

“Isl-I progenitors are present in the early postnatal heart, but disappear with progressing age,” says Dr. Morrisey. “Given the extreme rarity of these cells and their ability to act as progenitors of mature cardiac myocytes, the capacity of Wnt signaling to expand this population may prove to be useful in future work to harness the ability of these cells to regenerate damaged cardiac tissue.”

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PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.

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