Self-Organization as a Tool in Mammalian Tissue Engineering

Abstract

The end goal of most efforts in tissue engineering is the production of an artificial tissue or organ that is as similar as possible to the corresponding natural structure. So far, most approaches to this have involved combining cells with artificially-sculpted, spun or printed scaffolds. The approach works well for anatomically-simple, matrix-rich structures such as connective tissue, both in culture and in vivo. The visually-striking example of an engineered ‘human ear’ on the back of a mouse (Cao et al., 1997) brought much public attention to the idea. Scaffold-based tissue engineering has since found valuable clinical use in the production of new cartilage (Andereya et al., 2006), ligaments (Vunjak-Novakovic et al., 2004), vessels (Lovett et al., 2010), bladder wall (Atala, 2011) and nipple (Cao et al., 1998). Some of the most significant clinical requirements for effective tissue engineering concern not matrix-rich, simple tissues such as connective tissue, but very intricately-arranged complex organs that consist of many cell types, precisely located and in intimate contact with one another. Outstanding amongst these, in terms of clinical urgency, is the kidney, a fragile organ that regenerates itself very poorly, and which is damaged irreversibly by a large range of toxins, including some medicines. The demand for transplantable kidneys far exceeds their supply: in the UK alone, there are about 6,500 people on the waiting list, many leading fairly miserable lives in which they spend many hours per week hooked up to a dialysis machine. Being able to engineer organs such as kidney and pancreas promises a very positive impact on the lives of many patients, particularly if the engineering could be done from the patient’s own stem cells. There are, though, significant problems in extending scaffold-based techniques to organs such as these. The kidney, for example, consists of at least sixty-four distinct cell types (Little et al., 2007) and these are arranged not haphazardly but in very precise order along intricately folded and branched tubules, vessels and stroma (Fig 1). Even if a scaffold could be laid down by some highly-developed three-dimensional printing process to pattern accurately the basement membranes of each of a hundred thousand nephrons, ten thousand collecting ducts and a corresponding number of vessels, it is difficult to see how cells would enter each tube in the appropriate order to populate each segment with the correct type of cell. Kidneys do not normally develop by cells moving into a pre-made scaffold, so there is no reason to suppose that their cells would have evolved the ability to do this even if a scaffold could be provided for them. In normal life, there may be some limited movement of cells along tubules