By David N. Leff

Dig these words, penned in 1892 by a radical feminist and prominent author named Charlotte Perkins Gilman (1860-1935): "There is no female mind. The brain is not an organ of sex. As well speak of a female liver."

Now these words from transplant surgeon G. Melville Williams, chief of vascular surgery at Johns Hopkins University Hospital in Baltimore: "Interestingly," he told BioWorld Today, "[our research] suggests that the liver endothelium is unique. Those results were confirmed, at least in part, in some of our liver transplants done across sex differences. Where we could look for male bone marrow cells in patients given a female donor liver, we find them in the venous endothelium."

To which transplant surgeon Vivian McAlister added: "The venous endothelial cells line the lumen of the blood vessels that feed the liver. They're important in vascularized graft organs because they are the point of contact between the recipient and the donor graft. And the endothelium is that barrier."

McAlister, at Dalhousie University in Halifax, Nova Scotia, observed, "There's always been speculation about the role of this epithelium. One long-standing theory holds that if there were recipient replacement with donor blood-vessel endothelium, the grafts would appear to the recipient as if they were native organs, and therefore there would be no organ rejection.

"People have recently reported seeing this," McAlister continued, "in grafts that had undergone vascular rejection in kidneys, and not so much in other grafts that did not experience rejection. Williams and I have looked for it in livers and kidneys, but found it mainly in the liver venous endothelium. The liver," he explained, "is fed by portal veins, hepatic veins and the hepatic artery. But in the central venous endothelium we found occasional replacement by recipient cells of the donor blood vessels."

Williams and McAlister are co-senior authors of a paper in the current issue of The Lancet, dated March 24, 2001, titled: "Repopulation of liver endothelium by bone marrow-derived cells."

Unlike most tissues of the human body, the liver - its largest internal organ - is promiscuously capable of regenerating portions of its mass lost to removal or trauma. (See BioWorld Today, Feb. 22, 2000, p. 1.)

Smart Liver Trims, Swells New Mass To Fit

"The ongoing debate about the liver's special position," McAlister pointed out, "is whether it's about the organ's physical capacity or rather a special physiological capacity. In terms of regeneration," he went on, "there are two effects, both hitting on these arguments. One is that the liver already has a large capacity without regeneration, but also it does regenerate to size. If you remove parts of it, it will grow back to fit. So it has a large capacity, and it can regain that capacity after injury.

"The second thing," McAlister continued, "is that in the process of regrowing the bits and pieces that have been removed or damaged, obviously there must be a large amount of endothelial cell outgrowth. And it may well be that during this period there is an opportunity for recipient replacement of donor cells, giving the transplant a privileged position with respect to rejection.

"There are so-called pathotrophic factors - among others in the intestinal blood - that drain into the liver and stimulate its regeneration. It seem that these factors also have a role in maintaining liver size. So if you have some of your liver removed, these factors enlarge the whole organ back up to its right size. But for the donors of more than enough replacement fragments, the same factors shrink the now outsize liver to its correct dimensions."

In six needle biopsies of livers transplanted from female donors into male recipients, the co-authors and their postdoctoral fellow, Zu-hua Gao, found male Y chromosomes in the veins vascularizing the endothelial cells of the female donor organs.

So, to study the origins of the cells responsible for remodeling the donor liver epithelium, they created male-to-female bone marrow chimeric mice. "We just watched," Williams recounted, "to see if there was a population of recipient cells that went into the native liver and took up replaced endothelial cells - and we did find them. Our evidence would suggest they are stem cells from the bone marrow that can differentiate into the specialized cells in the endothelium. By doing a bone marrow replacement we were able to show where those particular cells come from."

Avoiding Immunosuppressant Life Sentence

As for putative clinical payoffs from these findings, McAlister commented, "Knowledge is very important to the development of therapeutic strategies. The goal of many researchers in this area is to do transplantation without the necessity for lifelong immune suppression. So I think our findings will allow us to begin to understand if a patient has truly reached tolerance. But another area of our research looks at the different immune suppressant drugs that we are currently using, to see if one particular regimen may favor graft maintenance over another."

"Up till now," Williams pointed out, "our findings remain speculative. They may provide some explanation, for example, why the liver really does need to be a rather privileged organ in transplant terms. The recipients of liver rarely undergo the chronic rejection that we experience with kidneys, heart and lungs. And perhaps this is at least a partial explanation for that."

He made the added point, "This is a good model for studying other things. For example, where do other endothelial cells come from that are present in vascular connective tissue? The previous hypothesis is that they bud from pre-existing endothelium that's turned on in inflammatory response, where they could be challenged. So I think this is a model that I intend to work on pretty extensively here at Hopkins - I hope in continuing collaboration with McAlister and Gao.

"One thing that's interesting to me," Williams concluded, "is that there is a stem cell in the bone marrow that needs to assume the role of an endothelial cell, with all of its markings and trappings. So I'd like to explore the contributions of circulating cells to atherosclerotic plaque, which has been assumed to derive from the blood vessel itself." n

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