Unbreak that heart

Gladstone and Stanford collaborate on developing IPS cells to repair damaged heart muscle

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SAN FRANCISCO—A $10 million, seven-year grant funded by theNational Heart, Lung and Blood Institute (NHLBI) has empowered scientists atthe Gladstone Institute of Cardiovascular Disease (GICD) and StanfordUniversity School of Medicine to conduct research aimed at discovering howpluripotent stem cells, or iPS cells, can repair damaged heart muscle anddevelop regenerative medicine therapies for cardiac patients.


The ambitious collaborative effort will be conducted byinvestigators led by GICD Director Dr. Deepak Srivastava, and a Stanford teamled by Dr. Robert Robbins, professor and chair of cardiothoracic surgery.


However, the Gladstone-Stanford research project representsjust a fraction of a wide-ranging effort that includes the technology programsof 17 multidisciplinary teams in nine research hubs, coordinated out of theUniversity of Maryland-Baltimore. Each research team will receive approximately$10 million over seven years as part of the NHLBI Progenitor Cell BiologyConsortium.


NHLBI Director Dr. Elizabeth Nabel says the NHLBI iscommitted to stimulating stem cell research leading to regenerative therapiesfor the treatment of heart, lung and blood diseases.


"Important gaps remain in our understanding of stem andprogenitor cells, and this consortium holds great promise to expand ourknowledge and uncover therapeutic applications of great public impact," Nabelsays.


Stanford cardiac specialist Robbins says, "This consortiumbrings together the leading scientists in this field in a large-scarecoordinated effort that may be a 'Manhattan Project' of stem cell research. Theaim is to investigate and evaluate the potential of this for the major diseasesof our time."


The partnership between the two prestigious institutions isa good fit, Srivastava said.


"We had natural synergy in bringing Gladstone's expertise iniPS cells and cardiac cell differentiation together with Stanford's expertisein imaging cells in animals, doing preclinical trials on large animal andbioengineering," Srivastava says. "The personalities of the investigators arealso synergized, and we realized that together we can accomplish more—and havemore fun doing it. We hope to be able to efficiently guide induced pluripotentstem (iPS) cells to become heart cells, fashion them in a way that they can beintroduced into damaged hearts, test their efficacy in large animals andprepare for a clinical trial," Srivastava said.


Induced pluripotent stem cells are derived from adult stemcells, like the skin, that are manipulated to achieve embryonic-like qualities,he said. Stem cells from human embryos are pluripotent, meaning they candevelop into any cell type.


Molecular and biochemical analyses of normal and mutatedhuman genes, including the study of disease-specific iPS cells, provideinsights into the mechanisms underlying normal and abnormal cardiacdevelopmental decisions. This technology was developed by Gladstoneinvestigator Dr. Shinya Yamanaka.


Reprogramming adult cells to function like embryonic stemcells is one way researchers hope to create patient-specific cell lines toregenerate tissue or to study specific diseases in the laboratory, Srivastavasays.


Stanford has also found a different, rather unconventionalmethod of inducing pluripotent stem cells.


A study by Stanford researchers published online Sept. 8 inthe Proceedings of the National Academy of Science, found it was easier and just as safe to make stemcells from fat cells freshly isolated from patients; for instance, from cellspresent in liposuction "leftovers," than it was to make them from skin cells asother studies have done recently.


"Thirty to 40 percent of adults in this country are obese,"reported cardiologist Dr. Joseph Wu, the paper's senior author. "Not only canwe start with a lot of cells, we can reprogram them much more efficiently.Fibroblasts, or skin cells, must be grown in the lab for three weeks or morebefore they can be reprogrammed. But these stem cells from fat are ready to goright away."


Researchers and medical professionals believe there iscompelling evidence for urgency—since heart problems affect children, as wellas adults. Heart disease is one of the biggest killers in the civilized world,and as populations age, this trend will increase dramatically, Gladstoneresearchers stated in a public abstract. Currently, the only way to treatfailing hearts is with expensive and relatively ineffective drugs, or by hearttransplantation.


"Ideally, we would like to be able to regenerate sick ordead heart tissue," the researchers stated. "The best strategy would be to makenew heart cells that match the patients' cells (to avoid rejection), and injectthem into diseased heart so that they could regenerate the sick heart.Unfortunately, current strategies that are planned to do so are ineffectual."


If the approach of "reprogramming" stem cells into heartcells is successful, these newly generated stem cells could be used forregenerative therapies in the future, researchers say, thus saving the lives ofcountless heart attack and heart damaged patients.


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