Adult stem cells are self-renewing and can in principle be redirected to become multipotent—able to differentiate into, among other things, organ-specific tissues, such as cardiac cells and blood vessels, that are essential for organ regeneration. Researchers typically turn to bone marrow and sometimes to the heart or brain for adult stem cells. But these cells are rarer than diamonds. “I would probably have to remove the majority of a patient's bone marrow to get enough stem cells to eventually regenerate just a small piece of the heart,” says Rafii. In addition, the technology to grow enough adult stem cells to use in regenerating human organs simply doesn't exist.

Instead, Rafii and his team turned to spermatogonial progenitor stem cells in the testes. Usually, these cells make only sperm. But Rafii's experience with teratomas suggested to him that maybe the cells could be directed toward tissue repair or regeneration.

The researchers began with mice. “The challenge was to isolate the spermatogonial stem cells and then to reprogram them from making sperm only to making various tissues,” Rafii says.

The cells were not easy to identify. But in collaboration with researchers at Regeneron Pharmaceuticals, the team discovered a marker, called GPR125, on the surface of spermatogonial stem cells. Next came finding the right “feeder” cells to encourage the growth, reproduction, and conversion from spermatogonial stem cells to adult stem cells. Marco Seandel, a senior postdoctoral fellow in Rafii's laboratory and first author of the Nature paper, developed unique feeder cells from adult mouse testicular stroma cells (a type of connective tissue cell that supports the proliferation and differentiation of stem cells).

Something about the culture medium with the new type of feeder cells made it work. The challenge now, says Rafii, is “to identify the switch and find out how to turn it on. We feel we are very close.”

The ultimate challenge will be to determine whether the methods work with human spermatogonial stem cells. The team has already begun studies with testes tissue from a human organ donation program as well as tissue isolated from monkeys. They have also begun exploring whether a similar approach might work in reprogramming putative stem cells in ovaries, although that may be “a long shot,” Rafii says, because similar stem and progenitor cells are scarce and difficult to biopsy.

Yet, he's willing to make that gamble, he says. As he has learned through his experiences in life and in the lab, taking chances can pay off.

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