Final Activity Report Summary - IGF1ESC (Effect of the local isoform of IGF on epidermal stem cells, aging and skin diseases) Our project was aimed at testing the therapeutic potential of a local isoform of insulin like growth factor 1 (mIGF-1) in skin and hair regeneration. IGF-1 is a peptide hormone that is produced by almost all tissues in the body and plays an important role in body growth, development and metabolism. Animals, in which IGF-1 was removed, showed a range of phenotypes that included severe growth retardation and in some cases lethality. Mutations in IGF-1 gene were also linked to human growth impairments.Due to its ability to stimulate cellular growth and survival, IGF-1 is an attractive candidate to be used in therapy. In fact, therapeutic and regenerative potential of IGF-1 molecule is being tested in a variety of settings. However, systemic infusion of IGF-1 has lead to hypoglycemia, electrolyte imbalance and fatigue, due to the supraphysiological doses needed to attain stimulatory effects. In addition, IGF-1 has been implicated in cancerogenesis.Our laboratory had studied the regenerative potential of a locally acting form of IGF-1 (mIGF-1) in the muscle and in the heart by generating transgenic animals with localised expression on mIGF-1. In both cases, mIGF-1 did not alter normal tissue homeostasis. At the same time, it stimulated regeneration after injury by promoting cell survival and renewal, while reducing inflammation and scarring. In addition, aged muscle of transgenic animals escaped age-related atrophy, maintained muscle strength and retained regenerative capacity in response to injury. In the project we tested the ability of mIGF-1 to assist regeneration in the skin and hair by generating a transgenic mouse model (K14/mIGF-1) in which mIGF-1 is expressed by skin cells called keratinocytes, that normally do not synthesise IGF-1. Being local, we expected mIGF-1 to remain near the site of production and to influence the behaviour of cells that synthesise it. Accordingly, we did not detect an increase in serum levels of IGF-1 in transgenic animals. Histological evaluation of K14/mIGF-1 skin did not reveal pathological alterations during the first year of life.We next tested the effect of mIGF-1 on two types of regeneration: wound healing and hair cycling. Wound healing was accelerated in transgenic animals due to more rapid wound closure. This was likely to be due to ability of mIGF-1 to stimulate proliferation and migration of keratinocytes that participated in wound closure. The underlying scar tissue was not significantly different, supporting the local nature of mIGF-1 action. In addition, growth phase during the first hair cycling, a regenerative process that occurs in the skin throughout the life span was also accelerated. Transgenic mice showed earlier hair appearance, faster growth and resulting increase in the hair length. However, with age, 20 % of K14/mIGF-1 transgenic mice developed tumours. Tumours arose when mice reached 14 months of age. In our experiment, the onset of tumourogenesis and the frequency of cases was significantly decreased, as compared to another transgenic mouse model (BK5.IGF-1) in which a similar IGF-1 isoform was used. The likely explanation being reduced levels of mIGF-1 in K14/mIGF-1 animals. In both, K14/mIGF-1 and BK5.IGF-1 mouse lines, IGF-1 was produced throughout the life span, giving a prolonged and persistent delivery of this factor molecule. Thus, it is likely that with a lower dose and/or controlled time window of IGF-1 delivery tumour formation can be avoided. In summary, constitutive production of mIGF-1 by keratinocytes improves wound healing and accelerates hair formation and growth, while maintaining normal skin morphology and function in young and adult animals.
