Imagine that I have a daughter who at an early age develops type 1 diabetes. The beta cells of the islets of Langerhans are being destroyed by her own immune system. She will be dependent on insulin injections all her life. Now imagine I have a friend who while playing rugby suffers a broken neck and loses all use of his limbs – he will be a wheelchair user for the rest of his life. Finally, imagine a friend who has a new baby boy. Following a heel-prick blood test he is told that his son has Duchene’s muscular dystrophy – his son will be a wheelchair user by 12-13, and will probably die of pneumonia in his early twenties. These stories are all tragedies, but all could be cured by stem cell technology – we would just need to grow a new pancreas, a new spinal cord, or build new muscle. If we were like plants this would be easy – plant cells are totipotent – a leaf, stem or root cell can be isolated and cultured to form a whole new plant. Unfortunately our cells do not have this ability. Once human cells have differentiated to be a beta cell or a muscle cell, or any terminal differentiation state then they are very reluctant to de-differentiate. The discovery of stem cells, or at least pluripotent stem cells, gave hope that the dream of manufacturing cells and tissues to cure many conditions, such as those above, could be realised.
If we have a totipotent cell then the situation would be relatively simple – we simply need to find the cocktail of growth factors and cytokines which drive a particular differentiation pathway. This type of approach has been successful with the cells listed in Table 1. Some of the therapies resulting have been used to treat burn victims. Keratinocytes isolated from fresh human epidermis can be grown for weeks and, when combined with a supporting matrix such as a fibrin matrix, can be used to successfully treat severe burn victims. More recently cells isolated from the dermal papillae have shown potential for persuading bulge stem cells to regenerate hair follicles. Mesenchymal stem cells (MSCs) have been used in a variety of studies by staff in Chester. Prof. Johnson has been investigating the potential use of clinically relevant MSC populations for the development of new cell therapies, particularly for patients with spinal cord injury and for cartilage repair. Dr Wilson has been using MSCs and HUVECs to derive osteoblasts and adipocytes that enable her to study the secretome as a means to understand how these cells influence bone erosion. The adipocytes have the added potential to investigate metabolic rate in type 2 diabetes – an approach being taken by Dr Ireland and Prof. Williams.
Although successful approaches have been described, the various stem cells are not present in large numbers and the generation of large numbers can be a problem. The real potential for stem cells will come if we can successfully de-differentiate (or trans-differentiate) adult stem cells. Two organisms that are capable of this are the Salamanda, which is capable of re-growing excised limbs, and Planaria, a flat worm which is capable of re-growing any body part that is excised – including the head. These and other organisms provide useful models to understand differentiation, as it is hoped that these will indicate the types of switches that need to be flipped to reverse differentiation. Recently blood monocytes have been successfully persuaded to form chondrocytes. Monocytes are in plentiful supply so this is hopefully a significant step assuming it can be confirmed. However, this conversion required insertion of a variety of genes known to be involved in differentiation using a viral vector. The ability to perform this re-wiring without a virus would reduce concerns on safety when considering for the clinic.
This short piece has just touched the surface of this exciting area. There are problems to be overcome. However, we should expect to see significant strides made to deal with the tragedies highlighted in the first paragraph over the next 10 years.
By Professor John HH Williams