Stem Cells Need a Framework for Organ Functionality

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Stem Cell Research Puzzle

While much work has ensued with stem cells, one of the primary problems has been the development of these grown tissues into three-dimensional organ. That has been the focus of Drs. Soker of Wake Forest, Uygun of Mass General, and Ott of Harvard Med and Mass General, and Dr. Paolo Macchiarini of the University of Barcelona, among others.

These researchers have been working on scaffolding techniques as the means to effect organ regeneration for a while. Basically, this process means that a new organ is constructed using a framework upon which new cells adhere and grow. The scaffold, which is produced by subjecting an existing (cadaver) organ to cell removal via detergents (such as sodium dodecyl sulfate) , is comprised of collagen and the underlying vascular system. The existing blood vessels can then be used to perfuse the nascent organ with nutrients (and oxygen). By stripping off the existing cells, the antigens are removed; this would greatly reduce the problem of organ rejection. The source of donor tissue (the produced new organs) can be allogenic (derived from the donor) or autologous (the cells form the actual host); autologous cells would not require the use of immunosuppressant drugs.

In 2008, Dr. Macchiarini transplanted a trachea (windpipe), which was developed using this process. His multinational group presented its results in the Lancet. This proof of concept (in a human) is why this promising technique is still being studied for whole organs.

This is very similar to the work being done at Mass General under the direction of Dr. Korkut Uygun. This group reported their results in Nature Medicine, with further information presented last week at the American Association for the Study of Liver Diseases (Boston), via a poster session .

In the first paper, the organ was regenerated using hepatocytes (which repopulated the scaffold), and then transplanted into rats (without removing their existing livers), which functioned for several hours. Last week’s paper involved using two different cells- adult hepatocytes and microvascular endothelial cells. The recellularized liver displayed hepatic function at around 30% of the native liver in vitro as determined via albumin, urea and total bile acid secretion.

A similar approach was presented by Dr. Soker’s group at [paper 12, 325a] that same meeting last week. Drs. Soker, Wang, Atala, and Baptista reported on the decellularizing of an existing whole (ferret) liver, leaving its vascular system intact. The scaffold was then perfused via the portal vein (emplaced in a bioreactor) and then re-cellularized with (fetal liver and endothelial) stem cells for periods up to one week.

They found the endothelial cells had formed a monolayer on the vascular channels, with the fetal liver cells distributed through the scaffolding (with some 1 to 1.5 cm depth). By using two different types of stem cells, the researchers were able to recoat the blood vessels, as well as recellularize the liver. This use of two different stem cells provides a more complete framework for the “artificial liver”. The researchers compared the tissues of the recellularized livers to normal ones, as well as for their ability to express proteins and proper cell markers.

The goal of Dr. Soker’s group is to reconstitute about 30% of the adult liver, which is the bare minimum by which a human can be sustained. This study developed about 100 million liver cells; the normal human cell has 100 billion.

One can expect this technique to be expanded for use in the pancreas (with several complex structures), the kidney (20 different cell types), and even the heart.

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