Repairing Bladders with Bone Marrow Stem Cells and Bladder Acellular Matrix

The bladder is subject to several different types of conditions that can compromise its function. Cancer of the bladder can necessitate its removal. A congenital condition called exstrophy causes the bladder to protrude through a hole in the abdominal wall also requires surgical repair of the bladder. Finally, trauma to the bladder as in the case of trampoline athletes or people who have had surgical damage to the bladder, may also repair bladder repair.

In order to repair the bladder, extra tissue must be added to it. Finding tissue to act as bladder has not been easy. In the past, surgeons have used grafts from skin, bladder submucosa, omentum, dura, peritoneum, colon, small intestine, and synthetic polymers have been used to augment the bladder. All of these compounds have their pluses and minuses for reconstructing a bladder, but all of them do not appropriately recapitulate the mechanical, structural, and functional properties of the bladder.

Currently a surgical procedure called enterocystoplasty is the most effective surgical solution for augmentation of the bladder. This procedure uses a small piece of the large intestine to increase the size of the bladder, and while it certainly improves continence, it has several complications associated, which include, metabolic disturbances, urinary stones (urolithiasis), increased mucus production, infections and increased risk of cancer of the bladder. Is there a better way?

A collaborative research project between Daniel L. Coutu from ETH Zürich, in Basel, Switzerland, Wally Mahfouz, Oleg Loutochin, and Jacques Corcos from McGill University, in Montreal, Canada, Wally Mahfouz from Alexandria University in Alexandria, Egypt, and Jacques Galipeau from Emory University in Atlanta, Georgia examined the use of bladder a cellular matrices or BAMs in combination with bone marrow-derived mesenchymal stromal cells to repair bladders in laboratory animals.

BAMs consist of bladders from animals that have been completely stripped of their cells with detergents and enzymes. Once all the cells and cell remnants have been removed, these BAMs can be molded into the form of a bladder, after which cells are reapplied. BAMs contain all the chemical nooks and crannies for cells to find, attach to, then and differentiate. Also, the bladder is a relatively simple tissue in that it has an inner epithelium (urothelium) that sits on a basement membrane, a smooth muscle layer surrounding the urothelium, and an outer serosa layer that is an extension of the peritoneum that it covered by an adventitia of connective tissue. A bladder matrix devoid of cells has all the right structures for cells to occupy, bit it needs to be repopulated with cells.

Corcos and his collaborators purchased pig bladders from slaughter houses and subjected them to detergents and enzymes until no cells were left on them. Then they used mesenchymal stromal cells from the bone marrow of rats to reseed the bladders with new cells. These structures were then used to repair the bladders to laboratory rats whose bladders had been partially removed. All the animals were then tested for retention of urine, muscle tone, pressure tolerance, and other indicators of bladder function.

The results of these tests demonstrated that the engineered bladders not only worked, but worked quite well. Some animals only received the BAM without cells, and these animals had bladders that worked better than nothing, but not terribly well. However, the animals that received BAM + mesenchymal stem cells had bladders that, for all intents and purposes, showed normal function by 6 months after the procedure.

Another significant finding of this study is that none of the animals that received BAMs had to be given any anti-rejection drugs. The immune systems of these animals did not reject the animal-based matrices.

Finally, post-mortem examinations of these animal bladders established that smooth muscle regeneration and nerve and blood vessels regeneration was also robust in these animals.

Before this procedure can work in humans, it will need to work in larger animal systems. Rat urinary systems are similar to humans, but not the same. The large advance in this study is the observation that internal bladder tissues such as smooth muscle, nerves and blood vessels can be regenerated with mesenchymal stem cells. These stem cells probably secrete a variety of molecules that promote the growth of blood vessels and nerves into the bladder.

In the words of these authors: “we demonstrated the in vivo superiority of MSCs-seeded BAMs compared with unseeded BAMs in bladder tissue engineering. Our approach is fully translatable to large animals and humans, where autologous MSCs could be seeded on allogeneic, cadaveric or xenogenic BAMs. The method presented here is a viable alternative to current treatment modalities and should prevent most complications associated with them. This study demonstrates the superiority of MSCs-seeded BAM compared to BAM alone in bladder augmentation and provides a strong basis to test our novel approach in large animal models and eventually in humans.”