Chapter 3 Tissue homeostasis Anders Lindahl Chapter contents 3.5 Tissues where regeneration was not considered – the paradigm shift in 3.1 Introduction 74 tissue regeneration 79 3.2 Tissues with no potential of 3.6 Consequence of regeneration potential regeneration 76 for the tissue engineering concept 81 3.3 Tissues with slow regeneration time 76 3.7 Cell migration of TA cells 85 3.4 Tissues with a high capacity of 3.8 Future developments 86 regeneration 77 3.9 Summary 86 Chapter objectives: ● To know the definition of the terms ● To recognize a stem cell niche regeneration and homeostasis ● To understand that stem cell niches ● To recognize that different tissues have share common regulatory systems different regeneration capacity ● To understand that tissue regeneration ● To acknowledge that the brain and heart has consequences and offer are regenerating organs opportunities in the development of ● To understand how tissue regeneration tissue engineering products can be analyzed by labeling experiments CCH003.inddH003.indd 7733 11/29/2008/29/2008 33:18:21:18:21 PPMM 74 Chapter 3 Tissue homeostasis I ’ d give my right arm to know the secret of regeneration Oscar E Schotte, quoted in Goss (1991) . 3.1 Introduction Distal amputation The ability to regenerate larger parts of an organism Original is connected to the complexity of that organism. The limp lower developed the animal, the better the regen- eration ability. In most vertebrates, the regeneration potential is limited to the musculoskeletal system and Amputation liver. In the hydras (a 0.5 cm long fresh-water cnidar- ian) the regeneration is made through morphollaxis, a process that does not require any cell division. If a part of the organism is lost through traumatic injury, 7d other cells adapt to the new situation and the result is a smaller but fully functional hydra. 21d In higher organisms like Salamanders, belong- ing to the urodele amphibians (a family of adult 25d vertebrates that can regenerate their limbs after ampu- tation), the regeneration is initiated by epimorpho- 32d sis, a process characterized by dedifferentiation and high proliferation of the local cells. The epimorpho- sis process starts immediately after the amputation of 42d the limb when a wound epidermis is formed through the migration and proliferation of epithelial cells. In a zone underlying the epidermis, mesenchymal cells 72d (muscle, cartilage and bone) lose their phenotype and start to dedifferentiate into blastemal cells which are the progenitor cells of the regenerating limb. Within the blastema, the cells undergo proliferation and red- Figure 3.1 Tissue regeneration in salamander. ( From ifferentiation into the various cell types needed to Goss, R.J. Principles of Regeneration , NY: Academic regenerate the limb. During this process the initial Press, 1969 .) muscle cells show plasticity by being able to rediffer- entiate into muscle, cartilage and bone ( Figure 3.1 ). even adults have the ability to regenerate finger tips. This ability of limb regeneration has obviously Regeneration of these tissues mirrors embryonic con- been lost in humans although we have the capac- trol mechanisms of differentiation from stem cells. ity for regeneration after injuries in a few tissues In the skin, brain, bone and muscle of mammalians, such as the liver, where we are able to regenerate a a subset of the cell population are selected during substantial part if it is resected surgically, bone and embryonic and fetal life to be used during childhood connective tissue. Furthermore, young children and growth and for tissue regeneration throughout life. CCH003.inddH003.indd 7744 11/29/2008/29/2008 33:18:21:18:21 PPMM 3.1 Introduction 75 Box 1 Regeneration potential of tissues during lifetime ● 3 tons of blood ● 500 kg intestinal epithelium corresponding to 40 km of intestine This concept has also been demonstrated in the heart Tissue homeostasis tissue ( Laflamme et al ., 2002 ). Recruitment of cells Apoptosis, cell Embryonic development results in a determined from stem cell pool death cellular structure where each cell has its function in a specific place. During subsequent growth, where the organism becomes larger cells proliferate but within their determined fate. Some animals like the fish, continue to grow throughout life although mammals stop growing in size; although the cell proliferation Figure 3.2 In the tissue regeneration process there is continues resulting in a constant renewal of cells in a balance between cell proliferation and cell death. the body. All organs are developed by the end of the first tri- mester, and the process continues during the rest of The tissue maintenance also has to control the the gestation of the fetus growth, and after birth until supporting tissues for a specific organ: organs need the growth spurt in adolescence is over. Most people mechanical strength which is provided by the extra- consider this to be the end stage of human growth cellular matrix produced by the connective tissue but nothing could be more wrong. We stop growing, cells (fibroblast, chondrocytes, bone cells). Most tis- and throughout life cells and tissues in the human sue also need a blood supply provided by the capillar- body are exposed to internal and external stress- ies and lining endothelial cells as well as innervation factors which lead to injury and loss by apoptosis provided by the nerve cells. Cellular debris cleaning or necrosis. However, to sustain the function of and tissue defense against bacteria and viruses are the tissues, the affected cells need to be replaced provided by macrophages and lymphocytes. All of through a process called regeneration. During our these cells are necessary to support the specialized lifetime, we are growing at a constant rate with a cell cells of each organ; the cleaning process of the liver turnover of about 1% of the body weight each day cells, the muscle cell contraction in the heart and the (Box 1). specialized endocrine cells. In some sense the organs of the body can be char- The internal structure of each organ must maintain acterized as a cellular homeostasis where cells are the intricate mixture of cells although the specialized constantly produced in order to balance the con- cells are renewed. This is orchestrated by the internal tinuous cell death ( Figure 3.2 ). The balance between determination memory of each specialized cell and cell production and cell death must be properly its stem cells that pass the information on to its prog- maintained since even small differences will give dra- eny. However, the specialized cell is highly adaptive matic effects; if the liver cells produced exceeds the to the surrounding environment and can change its cell death by 1%, the liver weight would be equal phenotype. Articular cartilage chondrocytes can be to the initial body weight within a time period of isolated and propagated in monolayer cultures where 6–8 years. the typical type II collagen production is changed CCH003.inddH003.indd 7755 11/29/2008/29/2008 33:18:22:18:22 PPMM 76 Chapter 3 Tissue homeostasis to a type I connective tissue type. However, when functionally adaptive remodeling activity (which is reimplanted into a cartilage environment, these cells more active in growing bone), is dominated by high- turn on their type II collagen synthesis again. A sec- magnitude, high-rate strains presented in an unusual ond example of adaptation properties are the epider- distribution. Adaptation occurs at an organ level, mal skin cells where mechanical load gives a different involving changes in the entire bone architecture thickness of the skin. Just compare the back of your and bone mass. This process is continuously ongoing hand with the front of your palm or your foot soil. and results in a total turnover time of 3 years for the Bone tissue is also constantly adapting structurally to whole bone structure. the changing load of the tissue. Not all organs regen- Cartilage has a similar turnover rate over time, erate in the same way – instead different organs have although the individual matrix components are different rates of regeneration. renewed at various rates. The two major extracellu- lar components in articular cartilage, collagen type II and aggrecan, are relatively longlived in the tissue 3.2 Tissues with no potential of and as a consequence undergoes non-enzymatic regeneration modifications by reducing sugars, thus ending in accumulation of advanced glycation endproducts. Although our body has the capacity to regenerate These accumulated endproducts reflect the half life to a large extent, there are tissues with no or limited of the components that for collagen is estimated to capacity of regeneration. For example, the central part be 100 years and for aggrecan to be 3,5 years. The of our lens consists of lens lamellas that are embry- cellular turnover in cartilage is probably limited and onic fossils that will not have changed since they were the localization of stem cells in articular cartilage is developed during embryonal life. The cell populations so far undetermined. However, the common dogma of the photo receptor of the retina and the auditory of cartilage as homogenous tissue with only one cell organ of Corti are not regenerated. In mammals, all type, the chondrocyte, producing the extracellular cells in the auditory organ of Corti becomes termi- matrix consisting of mainly collagen type II fibres, nally mitotic by embryonic day 14 and a similar phe- and the high molecular weight aggregating prot- nomenon occurs in avian basal papilla by embryonic eoglycan aggrecan is changing. The tissue is instead day 9 and thus one would expect that neither avian heterogeneous with distinct cellular characteristics nor mammals would be able to regenerate audi- in different zones from the surface zone with flat- tory cells ( Rubel et al ., 1995 ).