StemCell Therapy

ScienceDaily (Apr. 1, 2012) The latest research developments to reprogram scar tissue resulting from myocardial infarction (MI) into viable heart muscle cells, were presented at the Frontiers in CardioVascular Biology (FCVB) 2012 meeting, held 30 March to 1 April at the South Kensington Campus of Imperial College in London.

In a keynote lecture Dr Deepak Srivastava outlined his approach that has been described as a "game changer" with the potential to revolutionise treatment of MI. For the first time at the FCVB meeting, Srivastava presented the results of his latest studies using viral vectors to deliver genes directly into the hearts of adult mice that had experienced an MI. The FCVB meeting was organised by the Council on Basic Cardiovascular Science (CBCS) of the European Society of Cardiology (ESC).

In his original "proof of principle" study, published August 2010 in Cell, Srivastava was able to show that all that was needed for the direct reprogramming of fibroblasts (a major component of scar tissue) into myocytes (heart muscle cells responsible for beating) was the delivery of three genes.

The work , which took place in a Petri dish, was considered groundbreaking since it showed for the first time that unrelated adult cells could be reprogrammed from one cell type to another without having to go all the way back to a stem cell state.

"Our ultimate hope is that, during the acute period following MI, patients will be able to receive direct injections of factors that transform the existing fibroblast cells in the "scar" into new myocytes. The resulting increase in muscle mass should help MI survivors to live more normal lives," explained Srivastava, who is director of the Gladstone Institute of Cardiovascular Disease in San Francisco, US.

Healthy heart tissue is composed of a mixture of several kinds of cells, including cardiomyocytes, which provide beating muscle, and cardiac fibroblasts, that provide architectural support to the myocytes. "When heart muscle cells become injured and die following an MI, patients have the major problem that these cells have little or no capacity for regeneration," explained Srivastava. Part of the process of remodelling that occurs following the injury is that fibroblast cells migrate to the site and create the scar.

"The process at first can be considered beneficial since without fibroblasts adding structural support damaged hearts would rupture. But later difficulties arise when the fibrotic scar doesn't contract like the muscle it has replaced. Reduced global contractility means the heart has to work much harder, and the extra stress can ultimately lead to heart failure and even death," said Srivastava.

One of the Holy Grails of cardiovascular research has been to replace these lost myocytes and return functionality to the heart. Some of the first approaches to be investigated were the introduction of stem or progenitor cells to the sites of injury.

"But many hurdles have been encountered including getting cells to integrate with neighbouring cells in the heart, and there have been concerns that residual "rogue" cells could persist with the potential to keep dividing and give rise to tumours," said Srivastava. "Harnessing the vast reservoir of fibroblasts already present in the heart, we felt, could overcome many of these issues. They've the big advantage they're already present in the organ and closely integrated with neighbouring cells."

In the address Srivastava, a paediatric cardiologist, explained how he had first got ahead of the game by "leveraging" knowledge from his work in embryo hearts. Over the past 15 years the focus of Srivastava's lab has been to identify genetic factors responsible for the formation of embryonic hearts.

Link:
Transforming scar tissue into beating hearts: The next instalment

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