CD&D

Stem cells — where to get them and how to grow them into the right cell type — have gotten much of the attention in the quest for making organs for transplantation. But getting any sort of tissue is not in itself enough: to grow an organ, the right cell types need to grow into the proper shape.

In effect, this means overcoming a key hurdle: Though researchers have found various ways to grow viable tissues in two dimensions, the development of organs require a robust three-dimensional architecture.

In the Jan. 13, advance online issue of Nature Medicine, first author Harald Ott, senior author Doris Taylor, and their colleagues at the University of Minnesota (Minneapolis/St. Paul), report one way to accomplish this: by providing a template scaffold from another organ.

“It’s one of those things that makes a lot of sense in retrospect,” Taylor, director of the center for cardiovascular repair at the University of Minnesota, told Cardiovascular Devices & Drugs’ sister publication BioWorld Today. The work is indeed the sort of research that seems deceptively obvious once someone has done it.

The team used detergents to remove the cells from dead rat and pig hearts — finding the right detergent requiring a lengthy trial-and-error discovery process, according to Taylor — leaving behind a scaffold of extracellular matrix that contained collagen, fibronectin and laminin.

That scaffold was then reseeded with immature heart cells and grown in a bioreactor while being perfused with culture medium containing high levels of oxygen.

The team found that, after eight days in the reactor, the hearts were able to contract in response to either electrical stimulation or drugs.

The work has obvious applications in heart transplantation. And the scaffolding technique works with other organs, as the research team has shown to date with organs including lung, liver, and kidney.

This gives it broader applicability in the realm of organ transplants, but also opens up a basic research use: different scaffolds are basically ready-made stem cell niches.

“This isn’t just about one organ,” Taylor said. “We can decellularize virtually any organ.” And this means that “we have the potential, for the first time, to ask questions about nature versus nurture for stem cells ... this is a great tool and a test bed to understand some science that we haven’t had an opportunity to understand.”

In other words, by mixing and matching scaffolds and stem cell types, researchers can determine what happens to a cardiac stem cell that finds itself in a kidney scaffold, and whether the response of embryonic and adult stem cells differ.

In the work reported in Nature Medicine, Taylor and her team used immature heart cells rather than stem cells to reseed the scaffolds, to give themselves a greater shot at success.

They also reseeded the scaffolds with endothelial cells, and found to their surprise that the endothelial cells were specific in colonizing the vasculature and ventricular cavities.

“The cues were retained, in the completely acellular scaffold, to tell the [endothelial cells] where they needed to be,” Taylor said.

For any organs that might ultimately be made for transplant using the technique, scaffolds could be procured from three sources.

One is pig hearts, just as current replacement valves are often from a pig donor. Human donors are another possibility; while the same shortage that exists for other organs would be an issue with scaffolds, Taylor said that scaffolds could possibly be used from deceased donors whose full hearts are not suitable for transplant.

Finally, and “most radically,” Taylor said that it might be possible to re-seed a patient’s own scaffold, keeping them alive with an artificial heart in the meantime.

Whether that would be able to convert a failing heart to a functional one is, of course, unclear at this point. But Taylor said that cell therapy, too, “begins to change the geometry of the heart,” making it a possibility that the scaffold of a failing heart could be given a new lease on life.

For now, the hearts beat with about a 50th of normal strength. But Taylor prefers to think of the glass as 2% full rather than 96% empty. She pointed out that the 2% was reached only eight days after reseeding, and that so far the team has reseeded with relatively few cells for a relatively short period of time.

“Every heart we do is better than the one before it, and the longer we wait the stronger it gets,” she said.

And because this is the very beginning of the road to final, full deveopment, there are a large number of parameters to fiddle with. “We’ve got the next year or two cut out for us just in terms of straightforward things we need do” to see whether they increase contractile strength.

“I may eat my words,” she acknowledged. “But I’m optimistic that it won’t be that difficult to optimize.”

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