Stem cells from adult bone marrow can, as well as replacing blood cells, differentiate into liver, heart, muscle, nerve and lung cells. Findings published earlier this month (August 2001) add another string to their bow: showing that these cells also have the potential to become kidney cells. In particular they can become the type of cells — tubular epithelial cells — that need replacing in patients with acute or chronic renal disease.

Enthused by the discovery, Nick Wright, head of the Imperial Cancer Research Fund's (ICRF) Histopathology Unit and one of the authors of the paper in the Journal of Pathology argues that doctors might eventually be able to use stem cells taken from a patient's own bone marrow to differentiate into kidney cells and use them to replace tissue damaged by cancer and other diseases, thus reducing the risk of a rejection in a transplant.

The aspiration — not only to find new therapies for kidney diseases, but also to persuade adult stem cells from many tissue types to become a whole range of tissues to replace damaged cells — is widespread among scientists. It is also a goal that will prove difficult to reach because the science is very much in its infancy. Many problems need to be solved before new therapies become a reality.

"While in some instances it looks as though we might be able to pull off some quite remarkable therapies with adult stem cells, it's really not clear at the moment whether any single thing will be easy to apply," says Ron McKay from the National Institute of Neurological Disorders and Strokes at the National Institutes of Health, in Bethedsa, Maryland.

Some 20 major types of adult stem cell in mammals, where they replace and regenerate old and damaged tissue. As well as bone marrow, stem cells have been found in tissues as diverse as the liver, pancreas, bone and cartilage and elements of the nervous system.

The real excitement began when it became clear that stem cells originating in one tissue could generate the cells of another. In 1999, a team led by Angelo Vescovi of the San Raffaele Hospital in Milan showed that mouse neural stem cells when cultured and placed into bone marrow, seemed capable of generating a variety of blood cell types. Further tests in animals have shown that stem cells from the central nervous system can differentiate to form cells found in the muscle, blood, intestine, liver and the heart. And both muscle and nerve-derived stem cells have been shown to generate bone marrow.

In the new work, Richard Poulsom and his ICRF colleagues studied the fate of bone marrow transplanted into mice and into people. After giving whole marrow from male mice to females, the team observed that some of the male marrow stem cells could form new renal tubular epithelial cells. The researchers made a similar observation in people — where stem cells from an extra-renal source regenerated tubular epithelial cells in female kidneys given to male patients.

"We cannot establish unequivocally that the recipient's bone marrow is the source of the renal parenchyma in the human studies, but this is one likely source," states the report.

These and other results encourage optimism, but there are significant barriers to be overcome before suitable transplant tissue can be grown on demand. For example, little is understood about the molecular mechanisms that drive the differentiation of these stem cells into different tissues, and in some cases the exact identity of the cells involved is not known.

The barriers can be broadly classified as 'quantitative' and 'qualitative' says Leonard Zon, a developmental biologist working with stem cells at the Children's Hospital in Boston, Massachusetts. Most stem cell results published to date show very inefficient contributions to organ renewal, he says. Exact yields are difficult to quantify because of the unknown number of stem cells in each transplant sample, and transformation efficiency seems to vary from tissue to tissue, but it is clear that ways of artificially enriching, amplifying or purifying the target stem cell populations will be needed.

This may not be as simple as it sounds — little is known about the cell-surface markers that identify stem cells capable of such transformation, and many stem cell populations such as those producing pancreatic eyelet cells have proven extremely difficult to grow in vitro.

Animal tests have shown that the rescue of liver, muscle and now kidney tissue with stem cells all need the organs to be severely damaged. More information is needed about the biochemical signals that attract stem cells to damaged tissues and prompt them to differentiate into the required cells by affecting their gene function and expression. This might be achieved by studying the biochemical markers crucial to embryo development and by developing animal models to follow how transplanted stem cells behave.

Another unknown is, will tissue grown from 'foreign' stem cells will be as viable as those growing from stem cells within the same tissue — whether they will make the correct functional products for instance. "Though I'm not too worried about that as transplanted cells generally do pretty well," Zon says.

The possible effects of stem cells on non-target tissues will also have to be investigated before human therapies can be considered for all but the most poorly patients. Poulsom's team, for example, which he says was "very surprised" to see marrow cells finish up in the kidney, will now concentrate on identifying where else in the body the transplanted marrow cells are directed to.

They are fairly confident, though, about the identity of the cell responsible for their marrow-kidney transformation: stromal stem cells. Recent results from Diane Krause's lab at Yale University School of Medicine showed that a single hematopoietic stem cell, the other major stem cell type in bone marrow, could engraft multiple organs including the lung, gut and the skin, but not the kidney.